Dissertations / Theses: 'Vitamin D Receptor (VDR)'

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Hill, Natasha Tremayne. "Vitamin D receptor and 1alpha, 25-dihydroxyvitamin D3 mediated regulation of DeltaNp63alpha." Wright State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1450456950.

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Xavier, David André Rodrigues. "Vitamin D receptor (VDR) gene polymorphisms and genetic susceptibility to thyroid cancer." Master's thesis, Universidade da Beira Interior, 2013. http://hdl.handle.net/10400.6/1630.

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Thyroid cancer is the most common endocrine malignancy and a complex disease with a largely unknown aetiology. Thyroid carcinomas are derived from thyroid follicular cells and parafollicular cells. The majority of thyroid cancer cases comprise both papillary (PTC) and follicular carcinomas (FTC). The evaluation of genetic susceptibility could give valuable information regarding the risk of thyroid cancer development. There are many genes associated with the thyroid function that modulates the risk of tumour development. Among them, is the vitamin D receptor gene (VDR), located on chromosome 12q12-q14, and includes eight protein coding exons (exons 2-9) and one untranslated exon (exons 1a-1f). The most common VDR polymorphisms investigated are FokI (rs10735810 C>T), located in exon 2 of VDR, BsmI (rs1544410 G>A) and ApaI (rs7975232 G>T), located in intron 8, and TaqI (rs731236 T>C), located in exon 9 of VDR. The importance of vitamin D and its receptor VDR, in many signalling pathways is well known. Therefore we aim to verify in which way VDR polymorphisms influence the predisposition for thyroid cancer development. The contribution of four well-known VDR polymorphisms (FokI, BsmI, ApaI and TaqI) for the genetic susceptibility of thyroid cancer in the Portuguese population was analysed, including haplotypes comparisons. The following parameters were studied: thyroid cancer type differences (PTC vs. FTC), age (≤45 vs. >45 years), gender (male vs. female), carcinoma size (≤10mm vs. >10mm), lymph node metastasis and distant metastasis multicentricity, and stage of cancer (I-II vs. III-IV). All the participants in the study were Caucasian Portuguese inhabitants, being subdivided into two groups: patients with thyroid cancer (N = 208) and a control group (N = 248). In conclusion, there were some statistically significant differences in some parameters assessed. However, the results considered were only those with a statistical significant p-value < 0.005, according to Bonferroni’s correction. Therefore, the results suggest that BsmI polymorphism genotype AA (p = 0.004) may influence lymph node metastasis or distant metastasis in patients with DTC. Moreover, the TT genotype (p = 0.004) of ApaI polymorphism may increase the predisposition for more aggressive phenotypes of DTC, since it is overrepresented in patients with more advanced cancer stages (III-IV).
O cancro da tiróide é, de todas as neoplasias endócrinas, a mais comum, revelando ser uma patologia complexa e com uma etiologia desconhecida em parte. Tem uma incidência mundial que tem tendência a aumentar, contabilizando cerca de 1.7% dos cancros diagnosticados. Adicionalmente, o cancro da tiróide é mais prevalente em pacientes de meia idade e idosos, onde mais de metade dos indivíduos diagnosticados têm uma idade superior aos 45 anos. Ademais, esta neoplasia endócrina é mais comum nas mulheres, com uma incidência de 3 a 5 vezes maior. Os nódulos que surgem na tiróide são diagnosticados em cerca de 5% da população adulta mundial, e podem ser adenomas ou lesões malignas. Os carcinomas da tiróide derivam quer das células foliculares da tiróide, bem como das células C, porém, a grande maioria deles tem origem nas células foliculares. De todas as variantes de carcinomas da tiróide, os carcinomas papilar e folicular da tiróide são os mais predominantes, sendo a variante papilar a mais comum de entre todos, seguida da variante folicular. Apesar da elevada incidência mundial de cancro da tiróide, a taxa de mortalidade associada permanece estável. O tratamento do cancro da tiróide é um processo multifatorial, envolvendo a combinação de terapias cirúrgicas, hormonais ou de medicina nuclear. Sabe-se que o cancro da tiróide, em especial os tumores diferenciados da tiróide, estão a aumentar de incidência em alguns países desenvolvidos. Existem muitos fatores de risco que aumentam a predisposição para este tipo de cancro, incluindo fatores genéticos com risco associado a esta patologia. A título de exemplo, o cancro diferenciado da tiróide está associado a uma forte hereditariedade, aumentando a suscetibilidade genética do indivíduo em desenvolver cancro de acordo com o seu historial familiar. Para além disso, a presença de polimorfismos genéticos podem determinar a suscetibilidade individual do indivíduo para o desenvolvimento de cancro da tiróide. Atualmente são conhecidos vários genes associados com a função tiroideia e que modulam o risco para a tumorigénese. O VDR é um membro da superfamília de recetores nucleares, sendo a única proteína com afinidade para a 1α,25-dihidroxivitamina D, também conhecida como calcitriol. Nos mamíferos, a expressão do VDR encontra-se aumentada em tecidos metabólicos tais como o intestino, rins, pele e glândula da tiróide. O impacto biológico do VDR surge quando este se liga aos seus elementos localizados nas regiões promotores dos genes alvo, interferindo assim em muitas ações celulares e moleculares que vão desde a regulação do metabolismo de cálcio até à regulação de péptidos antimicrobiais. Desta forma, a ação molecular da vitamina D/ VDR está envolvida na regulação mineral e homeostase óssea, modulação do crescimento, eventos cardiovasculares, prevenção de cancro e regulação de respostas imunes. Uma disfunção do VDR ou défice de vitamina D podem levar a consequências no desenvolvimento e saúde óssea assim como aumentar a predisposição do indivíduo para o desenvolvimento de algumas doenças crónicas, incluindo o cancro. Os polimorfismos associados ao gene VDR já provaram estar implicados como um fator principal de risco em vários tipos de cancro, tais como o cancro da próstata, mama ou cólon. Ao longo do tempo, estudos de associação têm sido feitos de modo a se poder correlacionar os polimorfismos genéticos e o seu impacto na saúde do indivíduo. Assim, no presente trabalho pretende-se estudar a suscetibilidade genética do cancro da tiróide associada aos polimorfismos do gene VDR. Neste trabalho, foram estudados quatro polimorfismos diferentes gene do VDR. Para tal, através do uso de enzimas de restrição, foi possível analisar áreas restritas do gene VDR, localizado no cromossoma 12q12-q14 de forma a se poder observar variações da sequência de DNA. Os quatro polimorfismos estudados no âmbito deste projeto foram o FokI (rs10735810 C>T), localizado no exão 2 do VDR, BsmI (rs1544410 G>A) e ApaI (rs7975232 G>T), localizados no intrão 8, e TaqI (rs731236 T>C), localizado no exão 9 do VDR. Estes quatro polimorfismos foram analisados com o objetivo de verificar de que forma influenciam a predisposição de um indivíduo para o desenvolvimento de cancro da tiróide. Desta forma, este estudo realizado na população Portuguesa, fez a análise destas variantes do VDR, e o seu impacto no desenvolvimento de cancro da tiróide de acordo com os seguintes parâmetros: tipo de cancro, idade de diagnóstico, sexo, dimensões do carcinoma, metástases ganglionares e à distância, multicentricidade tumoral, e estádios de cancro. Todos os participantes deste estudo foram indivíduos caucasianos de origem Portuguesa. Estes indivíduos foram divididos em dois grupos distintos. Um dos grupos foi composto por indivíduos com cancro diferenciado da tiróide (N = 208), provenientes do Instituto Português de Oncologia de Coimbra. O grupo de indivíduos saudáveis (N = 248), que constituíam o grupo controlo, consistiram em dadores voluntários de sangue Portugueses caucasianos, que não possuíam um historial clínico de cancro da tiróide. Após o recrutamento dos indivíduos e obtenção das amostras de sangue dos mesmos, procedeu-se a uma série de metodologias práticas que visaram como objetivo final genotipar as amostras recolhidas. A cada indivíduo, doente ou controlo, foi atribuído um número de código único, de forma a poder identificar e diferenciar a amostra em estudo. O processo clínico dos doentes foi registado com todos os dados necessários para este estudo. Quanto aos indivíduos saudáveis, estes permaneceram no anonimato, sendo apenas registado a idade, sexo, peso, altura e naturalidade. Após estes procedimentos de registo, o DNA genómico foi extraído das amostras de sangue recolhidas através do método de “salting-out”. De seguida o DNA extraído foi quantificado e armazenado. Para efeitos de genotipagem, o DNA de cada indivíduo participante no estudo foi submetido à técnica “polymerase chain reaction”, mais conhecida por PCR. Com este procedimento pretende-se amplificar o fragmento do gene VDR onde se encontra cada polimorfismo. Após a amplificação do fragmento do VDR que se pretendeu estudar, conforme o polimorfismo, procedeu-se à digestão enzimática utilizando a respetiva enzima. Desta forma, conseguimos determinar o genótipo do indivíduo, através da visualização desses produtos digeridos num gel de agarose de 3%. Para além deste método, a genotipagem foi também confirmada através da sequenciação de DNA, sendo utilizada uma amostra representativa de cada genótipo para cada polimorfismo. Terminada a genotipagem de todos os indivíduos participantes deste estudo, para os quatro polimorfismos do VDR, procedeu-se ao tratamento estatístico dos dados analisando os parâmetros acima referidos. Como resultados, verificaram-se, em alguns parâmetros, algumas diferenças de frequências dos polimorfismos. De entre esses resultados, nas comparações entre pacientes de sexo diferente, o genótipo GA do polimorfismo BsmI foi mais frequente no sexo masculino (p = 0.044). Na análise de metástases ganglionares e à distância, o genótipo AA (p = 0.004) do BsmI e o alelo A (p = 0.014) e o genótipo CC (p = 0.024) do TaqI foram mais frequentes no grupo de doentes com metástases. No estudo da multicentricidade tumoral, o alelo C (p = 0.041) do FokI, o genótipo AA (p = 0.013) do BsmI, e o genótipo CC (p = 0.017) do TaqI foram mais frequentes nos doentes com multicentricidade. No estudo dos estádios de cancro, os genótipos GT (p = 0.012) e TT (p = 0.004) do ApaI, e seu respetivo alelo T (p = 0.031) foram mais frequentes em doentes com estádios mais avançados. A correção estatística de Bonferroni para comparações múltiplas revelou que os resultados foram estatisticamente significativos apenas para o genótipo AA do polimorfismo BsmI, que parece estar envolvido na presença de metástases ganglionares em indivíduos com cancro diferenciado da tiróide. Para além disso, também o genótipo TT do polimorfismo ApaI revelou diferenças estatisticamente significativas, podendo estar associado a um estádio mais avançado de cancro da tiróide. Desta forma, os polimorfismos do gene do VDR podem servir como marcadores de risco úteis para pacientes com cancro diferenciado da tiróide, uma vez que estes já forma associados em outros tipos de cancro. No entanto, não é possível retirar conclusões a partir destes resultados uma vez que são necessários mais estudos que permitam compreender as ações celulares e moleculares do VDR. Para tal, estudos funcionais genómicos serão necessários, para que se possa clarificar de que forma os polimorfismos deste gene podem influenciar a suscetibilidade genética para o cancro da tiróide.

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Schuch, Natielen Jacques. "Relação entre as concentrações séricas da vitamina D, polimorfismos do gene do VDR e síndrome metabólica em adultos e idosos." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/6/6138/tde-20012012-093621/.

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Introdução - O receptor de vitamina D (VDR) é expresso em vários tecidos e quando este se encontra na sua forma ativada, modula a expressão de diversos genes. Esses incluem variações dos níveis circulantes de 1,25(OH) 2 D , variações na densidade mineral óssea, secreção e sensibilidade à insulina em resposta à glicose, suscetibilidade à diabetes tipo 1 e 2, obesidade, dislipidemias e hipertensão arterial. Atualmente, evidências têm sugerido o envolvimento da vitamina D com a síndrome metabólica. Objetivo - Investigar a concentração sérica da vitamina D e sua relação com a síndrome metabólica e avaliar a potencial associação entre estes fatores com a presença de polimorfismos no gene do receptor de vitamina D (VDR) em indivíduos adultos. Métodos - Trata-se de um estudo transversal, onde foram avaliados 372 indivíduos adultos. Foram coletadas amostras sanguíneas para dosagens laboratoriais da 25(OH)D 3 , PTH e exames bioquímicos relacionados à SM, além disso foram realizadas avaliações antropométricas (peso, altura, IMC). A síndrome metabólica (SM) foi classificada usando o critério proposto pelo National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). A resistência a insulina foi estimada pelo cálculo de HOMA IR e a função da célula pelo cálculo de HOMA . A 25(OH)D foi dosada por HPLC e a insuficiência foi determinada pelo ponto de corte da curva Roc (52,6nmol/l). Foram avaliados também PTH intacto e cálcio sérico. Os polimorfismos BsmI e FokI foram detectados através da digestão das enzimas de restrições específicas para cada polimorfismo e confirmados através da técnica PCR alelo específico (ASPCR) ou amplificação de mutação refratária (ARMs) nos indivíduos com e sem SM (52 por cento vs. 48 por cento , respectivamente). A análise estatística inclui construção da curva ROC, teste T de Student, testes de correlação, teste de equilíbrio de Hardy-Weinberg, ANOVA, regressão logística binária (Odds Ratio). Estas análises foram conduzidas no software SPSS para Windows, versão 18 e p < 0,05 foi considerado significante. Resultados - A idade média dos participantes foi 51(15) anos, o IMC médio 29(6) kg/m 3 2 e 48 por cento apresentaram SM. Como esperado, os 3 indivíduos com SM apresentaram maiores valores de idade 57(12) anos, IMC 32(6) Kg/m , circunferência de cintura 103(13) cm, pressão sistólica 138(17) mmHg e diastólica 83(10) mmHg, glicemia de jejum 98(12) mg/dl, triglicérides 165(76) mg/dl, índices HOMA-IR 2.2(1.7) e 116(95), e menores valores de colesterol HDL colesterol 41(11) mg/dl. Com relação às concentrações séricas de 25(OH)D propostas pela análise da curva ROC, 43 por cento dos indivíduos com SM e 57 por cento dos indivíduos sem SM apresentam insuficiência desta vitamina. Correlações entre 25(OH)D 3 3 com PTH (r = -0.153; p = 0.005) e com circunferência da cintura (r = -0.106; p = 0.05) foram observada em todos os participantes. Considerando os polimorfismos do gene VDR, nos pacientes com SM, não houve associação entre o polimorfismo BsmI e os componentes da SM, HOMA e IR, 25(OH)D e PTH. No entanto, indivíduos sem SM, mas com homozigose para polimorfismo BsmI (genótipo recessivo bb ), apresentaram concentrações mais baixas de 25(OH)D 3 3 do que aqueles com o genótipo BB normal. Além disso, os indivíduos com SM e heterozigose para o polimorfismo FokI (genótipo Ff) têm maiores concentrações de PTH e HOMA do que aqueles com genótipo normal FF. Nesse mesmo grupo, os indivíduos com o genótipo recessivo ff têm maior resistência à insulina do que aqueles com genótipo Ff. Por outro lado, os pacientes sem SM, mas carregando o genótipo Ff, apresentaram maiores concentrações de triglicerídeos e baixos níveis de HDL do que aqueles com genótipo FF. A presença de um alelo f no genótipo (Ff ou ff) é, aparentemente, o suficiente para aumentar os níveis de triglicérides e resistência à insulina, quando comparados ao genótipo normal FF. Conclusão - Os resultados demonstram que o polimorfismo FokI no gene VDR associa-se a resistência à insulina e maiores concentrações de PTH em pacientes que apresentam SM. Além disso, o polimorfismo BsmI associa-se a menores concentrações de 25(OH)D em indivíduos sem SM. Portanto, esses novos dados indicam que polimorfismos no gene do VDR estão associados a diferentes fenótipos dos componentes da SM
Introduction - The vitamin D receptor (VDR) is expressed in many tissues and when it is in its activated form modulates the expression of several genes. These include changes in circulating levels of 1,25(OH)2D3, variations in bone mineral density, sensitivity and secretion of insulin in response to glucose, susceptibility to type 1 and 2 diabetes mellitus, obesity, dyslipidemia and hypertension. Currently, evidences have suggested the involvement of vitamin D with the metabolic syndrome. Objective - To investigate the serum concentrations of vitamin D and its relationship with metabolic syndrome (MS) and to evaluate the potential association between these factors with the presence of polymorphisms in vitamin D receptor gene in individuals adults. Methods - This is a cross-sectional study, which evaluated 243 adults and elderly. We collected blood samples for measurements of 25(OH)D3, iPTH, biochemical tests related to MS, and anthropometric evaluation (weight, height, BMI) were also assessed. MS was classified using the criteria proposed by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Insulin resistance and cell secretion were estimated by calculating HOMA IR and HOMA , respectively. The 25(OH)D3 was measured by HPLC and insufficiency was determined by the Roc curve cut-off (52.6 nmol/L). Intact PTH and serum calcium were also evaluated. The BsmI and FokI polymorphisms were detected by enzymatic digestion with specific enzymes and confirmed by allele specific PCR (ASPCR) or amplification of refractory mutation (ARM) in individuals with or without MS (52 per cent vs. 48 per cent , respectively). Statistical analyses include construction of Roc curves, Student T test, correlation tests, Hardy-Weinberg test, ANOVA, binary logistic regression (odds ratio), and TwoStep Cluster. These analyses were conducted with SPSS for Windows, version 18 and p < 0.05 was considered significant. Results - The mean age of participants was 51(15) years, mean BMI was 29(6) kg/m2, and 48 per cent of individuals presented MS. As expected, subjects with MS showed higher values of age (57(12) years), BMI was 32(6) kg/m2, waist circumference was 103(13) cm, systolic blood pressure was 138(17) mmHg, diastolic was 83(10) mmHg, fasting glucose was 98(12) mg/dl, triglycerides was 165(76) mg/dl, HOMA-IR was 2.2(1.7), HOMA was 116(95), and lower levels of HDL cholesterol was observed (41 mg/dl(11)). With respect to serum 25(OH)D3 proposed by ROC curve analysis, 43 per cent of individuals with MS and 57 per cent of individuals without MS presented insufficiency of this vitamin. Correlations between 25(OH)D3, iPTH (r = -0,153, p = 0.005), and waist circumference (r = -0,106, p = 0.05) were observed in all participants. Considering the VDR gene polymorphisms, in patients with MetSyn, there is no association among BsmI polymorphism and components of MetSyn, HOMA IR and , 25(OH)D3, and PTH. However, subjects without MetSyn, but with homozygosis for BsmI polymorphism (recessive bb genotype), presented lower levels of 25(OH)D3 than those with normal BB genotype. In addition, individuals with MetSyn and heterozygosis for FokI polymorphism (Ff genotype) have higher concentrations of PTH and HOMA than those with normal FF genotype. In this same group, subjects with the recessive ff genotype have higher insulin resistance than those with Ff genotype. On the other hand, patients without MetSyn, but carrying the Ff genotype, have higher concentration of triglycerides and lower levels of HDL than those with FF genotype. Interestingly, the presence of one allele f in the (Ff or ff) genotype is apparently enough to increase triglycerides levels and insulin resistance, when compared to the normal FF genotype. Conclusion - The results show that FokI polymorphism in the VDR gene is associated to insulin resistance and higher concentrations of PTH in patients with MetSyn. Moreover, BsmI polymorphism is related to a lower concentration of 25(OH)D3 in individuals without MetSyn. Therefore, the results indicated that VDR gene polymorphisms are associated to different phenotypes of MetSyn components

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Kommagani, Ramakrishna. "DIFFERENTIAL REGULATION OF VITAMIN D RECEPTOR (VDR) BY p53, p63 AND p73." Wright State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=wright1239687284.

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Caus, Enríquez Maite. "La ausencia de VDR en CMLV previene la calcificación vascular en ERC: Potencial rol del miR-145a." Doctoral thesis, Universitat de Lleida, 2021. http://hdl.handle.net/10803/671528.

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La calcificació vascular (CV) es una complicació molt prevalent en la malaltia renal crònica (MRC) i s’associa amb una alta mobilitat i mortalitat en pacients amb MRC. El receptor de la vitamina D (VDR) s’ha considerat que té un rol important en la diferenciació osteoblástica de les cèl·lules de múscul llis vascular (CMLV), tot i que el mecanisme concret encara no està clar. A més a més, la capacitat de VDR per influir en l’expressió de varis microRNAs (miRNAs), així com la gran quantitat de miRNAs presents en les CMLV, ens fa enfocar-nos en aquestes petites molècules com importants reguladores de la diferenciació i modulació fenotípica de les CMLV. L’objectiu d’aquest estudi va ser avaluar l’efecte de la deficiència de VDR en la calcificació vascular en MRC i la possible implicació del miR-145a en aquest procés. Vam confirmar un increment de tinció immunohistoquímica de VDR juntament amb un nivells augmentats de calci en arteries epigàstriques de pacients amb MRC comparat amb arteries de donants sans. Els ratolins amb nefrectomia 5/6 també mostraven alts nivells de calci arterial i de tinció immunohistoquímica de VDR comparat amb els ratolins controls. Els ratolins knockout condicionals per VDR en CMLV (Cre+ VDRlox/lox) sotmesos a una nefrectomia i tractats amb dieta alta en fòsfor i calcitriol van mostrar nivells significativament més baixos de contingut de calci, expressió d’osteopontina i lamin A, així com uns nivells més alts d’expressió de SOST comparat amb ratolins Cre+ VDRwt/wt amb el mateix tractament. A més a més, els ratolins Cre+ VDRwt/wt amb ERC i CV mostraven significativament nivells més baixos d’expressió arterial del miR-145a comparat amb els ratolins amb una eliminació específica de VDR en CMLV. In vitro, les CMLV VDRwt tractades amb medis calcificants mostraven nivells més alts de calci que les CMLV VDRko, juntament amb un increment de OPN a nivell de mRNA i proteïna. Els nivells del miR-145a disminuïen en CMLV amb condicions calcificants, tant en VDRwt com en VDRko, contràriament als resultats in vivo. Mitjançant la transfecció del miR-145a vam detectar un lleuger descens de la calcificació i de l’expressió de OPN en condicions calcificants. Concloem que l’eliminació del VDR de les CMLV protegeix enfront la calcificació vascular en MRC i que els mecanismes que regulen aquesta CV poden involucrar al miR-145a.
La calcificación vascular (CV) es una complicación muy prevalente en la enfermedad renal crónica (ERC) y se asocia con la alta morbilidad y mortalidad en estos pacientes. El receptor de la vitamina D (VDR) se ha considerado que tiene un rol importante en la diferenciación osteoblástica de las células de musculo liso vascular (CMLV), aunque el mecanismo preciso aún no es claro. La capacidad de VDR para influenciar la expresión de varios microRNAs (miRNAs), así como la gran cantidad de miRNAs presentes en CMLV, nos hizo prestar atención a estas pequeñas moléculas como posibles reguladoras del cambio fenotípico de las CMLV. El objetivo de este estudio fue evaluar el efecto de la deficiencia de VDR en la calcificación vascular en ERC y la posible implicación del miR-145a en este proceso. Confirmamos un incremento de tinción inmunohistoquímica de VDR juntamente con unos niveles más altos de calcio en arterias epigástricas de pacientes con ERC comparado con arterias de donantes sanos. Así como también, ratones con nefrectomía 5/6 mostraban altos niveles de calcio arterial y tinción inmunohistoquímica de VDR comparado con los ratones controles. Los ratones knockout condicionales para VDR en CMLV (Cre+ VDRlox/lox) sujetos a una nefrectomía y tratados con dieta alta en fosforo y calcitriol, mostraron niveles significativamente disminuidos de contenido de calcio, de expresión de osteopontina y lamin A, así como unos niveles más altos de expresión de SOST en arteria comparado con los ratones Cre+ VDRwt/wt con el mismo tratamiento. Además, los ratones Cre+ VDRwt/wt con ERC y CV, mostraron una disminución significativa del miR-145a comparado con los ratones con Cre+ VDRlox/lox. In vitro, las CMLV VDRwt con medios calcificantes mostraron niveles más altos de calcio que las CMLV VDRko, junto con un incremento de OPN. Los niveles del miR-145a disminuían en CMLV con condiciones calcificantes, tanto en VDRwt como en VDRko, contrariamente a los resultados in vivo. Mediante la transfección del miR-145a detectamos un ligero descenso del calcio y la expresión de OPN en condiciones calcificantes. Concluimos que la eliminación de VDR de las CMLV previene la calcificación vascular en ERC y que los mecanismos que regulan esta CV pueden involucrar al miR-145a.
Vascular calcification (VC) is a highly prevalent complication of chronic kidney disease (CKD) and, when present, is associated with the higher morbidity and mortality in CKD patients. Vitamin D receptor (VDR) has been proposed to have an important role in the osteoblastic differentiation of vascular smooth muscle cells (VSMCs); nevertheless the precise mechanism is unclear. The potential of VDR to influence widespread microRNAs (miRNAs) expression, as well as a myriad of miRNAs present in VSMCs drew attention to these small molecules as important regulators of VSMCs differentiation and phenotypic modulation. The aim of this study was to evaluate the effect of VDR deficiency on vascular calcification in CKD and the possible involvement of miR-145a in this process. We confirmed an increase of VDR immunostaining together with higher calcium in epigastric arteries from CKD patients compared with arteries from control non-CKD donors. We next analysed arteries from mice subjected to 5/6 nephrectomy. CKD affected mice showed higher levels of calcium content and VDR immunostaining in their arteries compared with control mice. VSMC-VDR conditional knockout mice (Cre+ VDRlox/lox) subjected to a subtotal nephrectomy and treated with high phosphate diet plus calcitriol showed significantly lower levels of vascular calcium content, osteopontin and lamin A expression, as well as markedly higher levels of SOST expression compared with their counterparts (Cre+VDRwt/wt) on the same treatment. Cre+VDRwt/wt mice affected by CKD and presenting VC showed significantly lower levels of expression of arterial miR-145a compared with mice with targeted deletion of VDR in VSMCs. In vitro, VDRwt VSMCs treated with calcification medium demonstrated higher levels of calcification than VDRko VSMCs, alongside an increased OPN. Levels of miR-145a decreased in VSMC with calcification conditions, both in VDRwt, which developed calcification, and in VDRko in which we didn’t detect calcium previously, contrarily to in vivo results. Through miR-145a transfection we detect a slight decrease in calcium and OPN expression in calcification conditions We conclude that VSMC’s VDR elimination prevents vascular calcification in CKD and that the mechanisms regulating VC might involve miR-145a, which warrant further investigations in this direction.

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Han, Shuxin. "VITAMIN D RECEPTOR REGULATION OF CHOLESTEROL 7α-HYDROXYLASE GENE TRANSCRIPTION AND BILE ACID SYNTHESIS IN HUMAN HEPATOCYTES." Kent State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=kent1257459841.

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Jain, Reema. "When too much sun is never enough: Association of the VDR gene polymorphisms with insulin resistance." AUT University, 2010. http://hdl.handle.net/10292/990.

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The metabolism of vitamin D commences with exposure of the skin to sunlight. The growing recognition of its role in insulin resistance, autoimmune disorders, infections, cancer, as well as the health of cells that influence physical and mental function have profound implications on how we define vitamin D requirements and why we should care whether they are met or not. Most of the actions of vitamin D are mediated by the vitamin D receptor (VDR), a protein whose gene sequence can vary, giving rise to polymorphic forms which are potent enough to affect the binding capacity of this protein to vitamin D. Some of these polymorphic forms of VDR gene may be associated with reduced effectiveness of vitamin D and hence predispose individuals to diseases such as type 2 diabetes and insulin resistance. An earlier study, the Surya Study, looked at the responsiveness of the South-Asian women living in Auckland to vitamin D. The research described here is an extension of this study and its focus was to identify the associations/linkages between certain polymorphic forms of the VDR gene and the disease conditions and intervention responsiveness in the same women. The first objective was to compare two well known techniques for genotyping single nucleotide polymorphisms (SNPs) of the VDR gene at the 3’ end, namely BsmI, ApaI and TaqI: the newer real-time polymerase chain reaction (qPCR) and the traditional restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) techniques. This comparison was performed to evaluate alternative methods for genotyping which consumed less time than RFLP-PCR. When the presence of each polymorphism by both the techniques was compared in this cohort of South-Asian women, it was found that RFLP-PCR proved to be a more reliable technique than qPCR for genotyping the VDR gene. Another objective of this project was to investigate the prevalence of the above three polymorphisms along with Cdx-2 and FokI SNPs which are present at the 5’ end of the VDR gene, in the population under study and their possible association with phenotypes such as vitamin D responsiveness and insulin resistance. These women were screened and biochemical data was collected during the earlier Surya Study. Of these, eighty-one women were then selected for intervention based on them having high insulin resistance (HOMA-IR>1.93) and serum 25(OH)D<50 nmol/L. Out of these eighty-one women, forty-two were given vitamin D supplement and thirty-nine were given a placebo for six months. Baseline and endpoint measurements included insulin resistance (HOMA-IR), insulin sensitivity (HOMA2%S) etc. How each individual responded to treatment in the intervention group was analysed in the context of the polymorphisms that they had. An association of insulin resistance with BsmI, ApaI and TaqI SNPs was observed in this cohort of 239 women. The response to insulin resistance in the vitamin D supplemented group significantly differed for FokI genotype compared to other genotypes. This explained why certain women responded to treatment better than the others. When the frequencies of the genotypes of these five SNPs of the VDR gene were compared to other studies of different ethnicities, the results of this study were consistent with few studies but contradictory to others. The possible reasons for these differences could be because of small sample size and different ethnicities under study due to which the frequency of alleles and hence the genotypes differed.

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Zhang, Xi [Verfasser], and Nadia [Akademischer Betreuer] Harbeck. "Potential new biomarkers for breast cancer : Vitamin D receptor (VDR) and BRCA1 proteins / Xi Zhang ; Betreuer: Nadia Harbeck." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1159879672/34.

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Joshi, Amod N. "Analysis of Archived Dried Blood Spots by Mass Spectrometry for Vitamin D and Real-time PCR for its Enzymes and Receptor." Wright State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1323273377.

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Chen, Jiaxuan. "The role of Pdia3 in vitamin D signaling in osteoblasts." Diss., Georgia Institute of Technology, 2012. http://hdl.handle.net/1853/50147.

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1a,25-Dihydroxyvitamin D3 (1a,25(OH)2D3) is a major functional metabolic form of vitamin D. 1a,25(OH)2D3 has drawn increasing attention due to its functions in addition to maintaining calcium phosphate homeostasis. It directly regulates mineralization by osteoblasts, matrix production and remodeling by chondrocytes, and contraction of cardiomyocytes. 1a,25(OH)2D3 and its analogues have shown beneficial effects in treating multiple sclerosis, diabetes and various types of cancer. In order to maximize the pharmaceutical potential of 1a,25(OH)2D3, a better understanding its cell signaling pathway is necessary. 1a,25(OH)2D3 regulates osteoblasts through both classical nuclear vitamin D receptor (nVDR) mediated genomic effects and plasma membrane receptor-mediated rapid responses. The identity of the plasma membrane receptor for 1a,25(OH)2D3 is controversial. Protein disulfide isomerase associated 3 (Pdia3) has been hypothesized as one of the putative plasma membrane receptors for 1a,25(OH)2D3. The overall goal of this thesis was to understand the general role and the molecular mechanism of Pdia3 in 1a,25(OH)2D3-initiated rapid responses, and to determine the role of Pdia3 and its dependent signaling in osteoblast biology. The results show that Pdia3 is required for membrane-mediated responses of 1a,25(OH)2D3. Moreover, both Pdia3 and nVDR are critical components of the plasma membrane receptor complex for 1a,25(OH)2D3. Finally, Pdia3 and signaling via Pdia3 regulate osteoblast differentiation and mineralization. Taken together, this study demonstrates the role of Pdia3 in rapid responses to 1a,25(OH)2D3 and osteoblast biology, reveals the unexpected complexity of the 1a,25(OH)2D3 plasma receptor complex and opens the new target, Pdia3, for pharmaceutical application and tissue engineering.

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Ferreira, Larissa Gorayb [UNIFESP]. "Avaliação dos polimorfismos do receptor de vitamina D (VDR) e do receptor sensor de cálcio (CaSR) em pacientes portadores de litíase renal." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/9114.

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Fundação Oswaldo Ramos
Alguns estudos identificaram uma associação entre nefrolitíase e os polimorfismos do Receptor de Vitamina D (VDR) ou do Receptor Sensor de Cálcio (CaSR). O objetivo deste estudo foi avaliar uma possível associação destes polimorfismos com a excreção de cálcio urinário (CaU) em pacientes litiásicos. O polimorfismo do VDR, detectado através da digestão com a enzima de restrição BsmI, e três polimorfismos do CaSR (G/T no codon 986, G/A no codon 990 e C/G no codon 1011), detectados através de sequenciamento direto, foram avaliados em pacientes litiásicos, sendo 100 hipercalciúricos (HCa) e 101 normocalciúricos (NCa). A frequência alélica do polimorfismo do VDR na amostra total foi: 16% BB, 49% Bb e 35% bb. A prevalência do genótipo bb foi significantemente maior nos pacientes HCa quando comparados ao grupo NCa (43 versus 27%). Em relação aos polimorfismos do CaSR, as três variantes alélicas (986S, 990G e 1011E) foram detectadas respectivamente em 5, 4 e 3% da amostra total e cinco haplótipos para os polimorfismos do CaSR foram identificados: 94% ARQ (selvagem), 3% SRQ, 1,5% AGQ, 1,0% ARE e 0,5% AGE. Nenhuma diferença estatística foi observada entre os pacientes NCa e HCa em relação à distribuição destes haplótipos do CaSR. Estes achados sugerem uma associação entre a excreção urinária de cálcio com o polimorfismo BsmI do VDR mas não com os três polimorfismos do CaSR em pacientes litiásicos.
TEDE
BV UNIFESP: Teses e dissertações

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BARBOSA, Alexandre Domingues. "Polimorfismos do gene codificante do receptor da vitamina d (vdr): associação com a susceptibilidade à osteoporose pós‐menopausa e gravidade da doença." Universidade Federal de Pernambuco, 2013. https://repositorio.ufpe.br/handle/123456789/12005.

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A osteoporose é uma doença esquelética caracterizada pelo comprometimento da resistência óssea, predispondo ao risco aumentado de fraturas. A resistência óssea reflete a integração de dois parâmetros principais: densidade e qualidade ósseas. É considerado um importante problema de saúde pública, devido às fraturas por fragilidade óssea e a sua associação com o aumento da mortalidade e morbidade, que resultam em um considerável gasto da economia global. As fraturas do corpo vertebral, quadril e punho são as fraturas típicas da fragilidade óssea gerada pela doença, com custo anual estimado em 20 bilhões de dólares por ano nos Estados Unidos e 30 bilhões de dólares por ano na União Europeia. As células ósseas formadoras de osso, os osteoblastos, possuem receptores para a forma ativa da vitamina D, que quando estimulados favorecem a renovação e manutenção da massa óssea. Além disso, na célula muscular esquelética, a vitamina D também atua através de receptores que envolvem o transporte de cálcio, a síntese proteica e a velocidade de contração muscular. Dessa forma, a vitamina D é de grande importância na função neuromuscular, na cinética da contração muscular e no equilíbrio, fatos que repercutem na capacidade de realizar movimentos rápidos que evitam quedas e possíveis fraturas em indivíduos portadores de baixa densidade mineral óssea. O objetivo desse estudo foi investigar o papel de polimorfismos do gene do receptor da vitamina D (VDR) na predisposição à osteoporose pós‐menopausa em pacientes do Estado de Pernambuco e na modulação do fenótipo patológico da doença. A amostra foi composta por 146 mulheres portadoras de osteoporose pós‐menopausa atendidas no serviço de Reumatologia do Hospital das Clínicas da UFPE; e o grupo controle formado por 95 voluntárias saudáveis da mesma região geográfica. Foram analisados 3 TagSNPs (Single Nucleotide Polymorphisms) no gene VDR : rs11168268 (A>G); rs1540339(C>T); rs3890733(C>T). Os TagSNPs estavam distribuídos em 3 diferentes regiões no gene, apresentando MAF (minor allele frequency) ≥ 10% e com base nas populações descendentes de Europeus e de Africanos. As análises estatísticas correlacionaram os genótipos/haplótipos com densidade mineral óssea (DMO); sítio da osteoporose (colo de fêmur, fêmur total e coluna vertebral); presença de fraturas por fragilidade; grupo étnico; número de quedas por ano; insuficiência e deficiência de vitamina D. Não foi constatada associação estatisticamente significante entre os TagSNPs testados e a osteoporose pós‐menopausa. Entretanto, após estratificação dos dados e correlação com as outras variáveis apresentadas pelas pacientes, foi observada associação ente os TagSNPs rs11168268 (A>G) e DMO de fêmur total (p = 0,042); rs1540339(C>T) e o grupo étnico de descendentes de europeus (p = 0,043); e entre rs3890733(C>T) e mulheres abaixo de 60 anos de idade (p = 0,043). Apesar da massa óssea ser influenciada por inúmeras citocinas e hormônios, micronutrientes, atividade física e o meio ambiente onde o indivíduo está inserido, a associação desses TagSNPs com DMO de fêmur total, etnia e idade entre as mulheres pós‐menopausadas, confirma a modulação genética do fenótipo da doença osteoporótica.

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Brito, Junior Rui Barbosa de. "Associação entre polimorfismos nos genes do receptor CD14, receptor de vitamina D (VDR) e HLA-DRB1 e doencças periodontal cronica." [s.n.], 2003. http://repositorio.unicamp.br/jspui/handle/REPOSIP/290046.

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Orientador: Silvana Pereira Barros
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Doutorado

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Santos, Betânia Rodrigues dos. "Estudo da associação entre polimorfismos do gene do receptor de vitamina D (VDR) e do SNP-71 A/G do gene 17 beta- hidroxiesteróide desidrogenase tipo 5 (HSD17B5) e variáveis clínicas, hormonais e metabólicas em pacientes com pubarca precoce e controles." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/31696.

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A pubarca precoce (PP) é definida como o desenvolvimento de pêlos pubianos antes dos 8 anos de idade em meninas e 9 anos de idade em meninos. Embora a PP não interfira diretamente com os eventos da puberdade, algumas evidências sugerem que estas meninas tenham maior risco para desenvolver, mais tarde, a Síndrome dos Ovários Policísticos (PCOS). A 17ß-hidroxiesteróide desidrogenase tipo 5 (17ßHSD5) é a principal responsável pela conversão de androstenediona em testosterona. Variações no gene que codifica para essa enzima, em especial os polimorfismos de nucleotídeo único (SNPs), podem estar relacionados com hiperandrogenismo e PCOS. A vitamina D, além dos efeitos sobre metabolismo ósseo, parece modular outras ações extra-esqueléticas, incluindo secreção e sensibilidade tecidual à insulina. A Vitamina D vem sendo associada com resistência insulínica e variantes do gene do receptor da vitamina D (VDR), vem sendo estudadas em populações de risco como no diabetes. No entanto, pouco se sabe sobre o envolvimento destes polimorfismos na PP. Os objetivos do presente trabalho foram: Avaliar os níveis de 25-hidroxivitamina D; determinar a frequência dos polimorfismos FokI, BsmI, ApaI e TaqI do gene do VDR e do SNP-71AG do gene da 17ßHSD5; verificar se existe associação entre esses polimorfismos com variáveis antropométricas, metabólicas e hormonais em uma amostra de pacientes com PP e controles do sul do Brasil. Foram arroladas 36 meninas com PP e 197 controles saudáveis. As genotipagens foram realizadas por PCR em tempo real para os SNPs -71AG, BsmI e FokI e por PCR-RFLP para os SNPs ApaI e TaqI. O SNP -71 AG do gene da 17ßHSD5 apresentou distribuição genotípica de 52,4% AA, 39,1% AG e 8,6% GG, sendo a frequência dos alelos A:G de 0,72:0,28. Analisando os dois grupos, verificamos uma maior freqüência do alelo variante (G) no grupo de meninas com PP quando comparadas aos controles (0,37 e 0,26, respectivamente), no entanto sem diferença estatística (p=0,054); não foram verificadas associações do polimorfismo com os dados clínicos e hormonais. As meninas com PP apresentaram níveis séricos de 25(OH)D inferiores aos das meninas controles (18,08±8,32 versus 21,27±7,03; p=0,032). Na análise dos polimorfismos, observou-se que o genótipo polimórfico GG do SNP ApaI TG, apresentou uma frequência maior em PP (30,6%) do que nas controles (16,2%) (Odds Ratio: 2,269; 95% Intervalo de Confiança: 1,015 – 5,076; p=0,042). Este genótipo foi também associado com níveis mais baixos de estradiol (35,30 (14,80 – 50,48) versus 12,22 (6,49 – 23,69); p=0,030) e testosterona total (0,52 (0,39 – 0,84) versus 0,20 (0,11 – 0,47); p=0,009) nas meninas com PP, mas não foi associado com os níveis de 25(OH)D. Por outro lado, verificou-se associação entre a presença dos polimorfismos TaqI TC (genótipo TC+CC) e BsmI GA (genótipo GA+AA) e níveis séricos de 25(OH)D mais elevados no grupo de meninas saudáveis (19,86±7,16 versus 22,55±6,69, p=0,007; 19,53±6,94 versus 22,88±6,76, p=0,001, respectivamente). Em conclusão, os dados deste estudo indicam que: 1) houve maior freqüência do alelo variante G SNP -71 AG do gene da 17βHSD5, com uma associação limítrofe desse alelo com o diagnóstico clínico de PP; 2) o polimorfismo ApaI TG associou-se com PP e parece estar modulando os processos esteroidogênicos nas meninas com PP; 3) houve uma interação entre os polimorfismos TaqI TC e BsmI GA e concentrações circulantes de vitamina D em meninas do sul do Brasil.
Precocious pubarche (PP) is usually defined as the development of pubic hair before the age of 8 in girls and age of 9 in boys. Although the PP does not interfere directly in puberty events, some evidence suggests that these girls have higher risk for the development of Polycystic Ovary Syndrome (PCOS) at later ages. The Type 5 17β-Hydroxysteroid Dehydrogenase (17ßHSD5) is the principal responsible for the conversion of androstenedione to testosterone. Variations in the gene encoding for this enzyme, especially Single Nucleotide polymorphisms (SNPs), may be related with hyperandrogenism, and PCOS. Besides the effects on bone metabolism, vitamin D appears to modulate other extra-skeletal actions, including secretions and tissue sensitivity to insulin. Vitamin D has been associated with insulin resistance and variants in the vitamin D receptor (VDR) gene, have been studied in populations at risk of Diabetes. However, little is known about these polymorphisms in the PP. The aims of this work were: to evaluate the levels of the 25-hydroxyvitamin D; to determine the polymorphisms FokI, BsmI, ApaI and TaqI in VDR gene and SNP -71AG in 17ßHSD5 gene frequencies; to asses if exist association between this SNPs and anthropometric, metabolic and hormonal characteristics in patients with PP and controls of the southern Brazil. Were enrolled 36 girls with PP and 197 healthy controls. Genotypic analyzes were evaluated by Real Time for the SNPs -71AG, BsmI and FokI and by PCR-RFLP for the ApaI e TaqI polymorphisms. Genotype frequency for SNP -71 AG of the 17ßHSD5 gene was 52.4% AA, 39.1% AG and 8.6% GG, A:G allelic frequency was 0.72:0.28. Analyzing both groups, higher frequency of the variant allele (G) in patient PP than controls (0.37 e 0.26, respectively) was found but without statistical difference (p=0.054); there were no associations between this polymorphism and clinical and hormonal features. PP girls have serum levels of 25(OH)D lower than those from control group (18.08±8.32 versus 21.27±7.03; p=0.032). The polymorphism analyze was observed that genotype GG of the SNP ApaI TG showed a higher frequency in PP (30.6%) than controls (16.2%) (Odds Ratio: 2.269; 95% confidence interval: 1.015 – 5.076; p=0.042). The same genotype was associated with lower estradiol (35.30 (14.80 – 50.48) versus 12.22 (6.49 – 23.69); p=0.030) and total testosterone levels (0.52 (0.39 – 0.84) versus 0.20 (0.11 – 0.47); p=0.009), in girls with PP. There were no association between this polymorphism and serum 25(OH)D. On the other hand, there was association between the presence of the polymorphisms TaqI TC (TC + CC genotype) and BsmI GA (GA + AA genotype) and higher serum 25(OH)D in the group of healthy girls (19.86 ± 7.16 versus 6.69 ± 22:55 , p = 0.007; 19:53 ± 6.94 versus 22.88 ± 6.76, p = 0.001, respectively). In conclusion, data from this study indicate that: 1) there was a higher frequency of the variant allele G of the SNP -71 AG of the 17ßHSD5 gene, with a borderline association of this allele with the clinical diagnosis of PP; 2) ApaI TG polymorphism is associated with PP and seems to modulate the processes steroidogenesis in girls with PP; 3) there was an interaction between the polymorphisms TaqI TC and BsmI GA and vitamin D concentrations in girls from southern Brazil.

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Ferrarezi, Daniela Andraus de Figueiredo. "Variações alélicas no gene do receptor da vitamina D (VDR) e risco de doença arterial coronariana em pacientes diabéticos tipo 2." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-05052011-142938/.

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A doença cardiovascular (DCV) é a principal causa de mortalidade e morbidade em pacientes portadores de diabetes mellitus tipo 2 (DM 2), estando associada com mais de 80% das mortes nesses pacientes. Portadores de DM 2 têm um risco três vezes maior em relação à indivíduos não diabéticos de desenvolver aterosclerose e suas complicações clínicas como infarto agudo do miocárdio (IAM), acidente vascular cerebral (AVC) e doença vascular periférica. O sistema endócrino da vitamina D regula a diferenciação e a proliferação de vários tipos celulares, além de possuir propriedades antiinflamatórias e antiangiogênicas. Assim, a vitamina D poderia ter um papel protetor contra as doenças degenerativas crônicas como a DCV. Estudos epidemiológicos sugerem que a deficiência de vitamina D está associada com doença arterial coronariana (DAC). As ações da 1,25(OH)2D3 são mediadas pela sua ligação ao seu receptor nuclear (VDR). O objetivo do presente estudo foi investigar as associações de polimorfismos de um único nucleotídeo (SNPs) no gene VDR com DAC em duas coortes de pacientes portadores de DM 2. Um total de 3.137 pacientes provenientes do estudo prospectivo DIABHYCAR (14,8% de incidência de DAC no seguimento) foi estudado. Uma outra coorte (NECKER - COCHIN) independente composta de 713 indivíduos portadores de DM 2 (32,3% dos quais tinham DAC) também foi avaliada. Três SNPs no gene VDR foram genotipados: rs1544410 (BsmI), rs7975232 (ApaI) e rs731236 (TaqI). Uma associação do alelo A de BsmI com casos incidentes de DAC (Hazard Ratio = 1,16; IC 95% = 1,05-1,29; p = 0,002) foi observada, assim como associações do alelo A de BsmI (p = 0,01) e do alelo C de TaqI (p = 0,04) com casos de DAC no início do estudo. O haplótipo AAC (BsmI / ApaI / TaqI) foi significantemente associado com aumento da prevalência de DAC no final do estudo, em comparação com o haplótipo GCT (Odds Ratio = 1,12; IC 95% = 1,02-1,28; p = 0,04). Associações do alelo A de ApaI (p = 0,009) e do alelo C de TaqI (p = 0,05) com DAC foram observadas no estudo transversal da coorte Necker - Cochin. Os resultados obtidos com os haplótipos também foram replicados nessa coorte (Odds Ratio = 1,33; IC 95% = 1,03-1,73; p = 0,03). Em conclusão, o haplótipo composto pelo alelo raro de BsmI, pelo alelo frequente de ApaI e pelo alelo raro de TaqI (AAC) foi associado a um maior risco de DAC em pacientes portadores de DM 2. Este efeito foi independente dos efeitos de outros fatores de risco cardiovasculares
Cardiovascular (CVD) disease is the leading cause of mortality and morbidity in patients with type 2 diabetes being associated with up to 80% of the deaths in these patients. Diabetic patients have a 3-fold higher risk than non diabetic individuals for developing atherosclerosis and its clinical complications such as myocardial infarction, stroke, and peripheral vascular disease. The vitamin D endocrine system regulates the differentiation and replication of several cell types and has antiangiogenic and antiinflammatory properties. Thus, it could have a protective role against chronic degenerative disorders such as CVD. Epidemiological studies suggested that vitamin D deficiency is associated with coronary heart disease. Actions of vitamin D are mediated by the binding of 1,25-(OH)2D3 to a specific cytosolic/nuclear vitamin D receptor (VDR). The present study investigated associations of VDR gene variants with coronary artery disease (CAD) in two cohorts of type 2 diabetic subjects. A total of 3,137 subjects participating in the 6-year prospective DIABHYCAR study (14.8% of CAD incidence at follow-up) were evaluated. An independent, hospital-based cohort (NECKER-COCHIN) of 713 diabetic subjects, 32.3% of whom had CAD, was also studied. Three single nucleotide polymorphisms (SNPs) in the VDR gene were genotyped: rs1544410 (BsmI), rs7975232 (ApaI) and rs731236 (TaqI). In the DIABHYCAR cohort, an association of the A-allele of BsmI with incident cases of CAD was found (Hazard Risk = 1.16; 95% C.I = 1.05-1.29; p = 0.002). Associations were also observed for the A- allele of BsmI (p=0.01) and C-allele of TaqI (p = 0.04) polymorphic variants with baseline cases of CAD. The AAC haplotype (BsmI/ApaI/TaqI) was significantly associated with increased CAD prevalence at the end of the study as compared with the GCT haplotype (Odds Ratio = 1.12; 95% C.I. = 1.02-1.28; p = 0.04). Associations of ApaI (p = 0.009) and TaqI (p = 0.05) alleles with CAD were observed in a cross-sectional study of the NECKER-COCHIN cohort. The haplotype results were also replicated (Odds ratio = 1.33; 95% C.I. = 1.03 - 1.73; p = 0.03). In conclusion, the haplotype composed by the minor allele of BsmI, the major allele of ApaI and the minor allele of TaqI (AAC) was associated with increased risk of CAD in type 2 diabetic patients. This effect was independent from effects of other known cardiovascular risk factors

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Nascimento, Rayner Anderson Ferreira do. "Relação entre polimorfismos nos genes VDR e MTHFR, marcadores inflamatórios e de estresse oxidativo e parâmetros clínicos com a ocorrência de retinopatia em diabetes mellitus tipo 2." Universidade Federal da Paraíba, 2015. http://tede.biblioteca.ufpb.br:8080/handle/tede/9435.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Diabetic retinopathy (DR) is an important cause of acquired blindness among diabetics. Clinical factors are related to the risk for DR, in addition, genetic markers have been investigated, among them VDR and MTHFR polymorphisms, however, the impact of rs1801131 and rs1801133 polymorphisms is still inconclusive, while for rs1544410 there is a shortage in the literature. In this work the relationship of polymorphisms rs1544410, rs1801131 and rs1801133 with DR was investigated by cross-sectional study in a sample of 109 individuals with type 2 diabetes (T2DM) duration between 5 and 10 years. After ophthalmological screening a group of 40 affected and 69 unaffected by DR was composed. Genomic DNA was extracted from buccal cells. Genetic data were obtained by PCR-RFLP and analyzed using Fisher's exact test. Blood sample and urine for metabolic markers determinations were obtained in 62 subjects and the mean values were compared to the allele and genotype distribution of rs1544410. There was no association between alleles or genotypes of polymorphisms rs1801131 and rs1801133 with RD. The polymorphic allele b and genotypic group Bb + bb of rs1544410 were more frequent in the affected group with mild significance: [OR 0.5 (95% CI 0.31-0.98) p = 0.0478] and [OR 3.4 (95% CI 1.07-10.9) p = 0.496], respectively. None of the clinical variables were associated with rs1544410 although a trend towards higher values of C-reactive protein in patients allele b has been identified but not statistically significant. In conclusion, this study suggests that the sample investigated rs1544410 polymorphism of the VDR was related to the risk of DR, but not rs1801131 and rs1801133 MTHFR polymorphisms.
A retinopatia diabética (RD) constitui importante causa de cegueira adquirida entre diabéticos. Fatores clínicos estão relacionados ao risco para RD, em adição, diversos marcadores genéticos têm sido investigados, dentre eles, polimorfismos do MTHFR e VDR. Atividade defeituosa desses genes podem atenuar mecanismos implicados na patogenia da RD, no entanto, o impacto dos polimorfismos rs1801131 e rs1801133 ainda é inconclusivo, enquanto que para o rs1544410 há uma escassez de estudos na literatura. Neste trabalho a relação dos polimorfismos rs1801131, rs1801133 e rs1544410 com RD foi investigada por meio de estudo transversal em amostra de 109 indivíduos com tempo de duração de diabetes mellitus tipo 2 (DM2) entre 5 e 10 anos. Após avaliação oftalmológica foi constituído um grupo de 40 afetados e 69 não afetados por RD. DNA genômico foi extraído de células bucais. Os dados genéticos foram obtidos por PCR-RFLP e analisados utilizando o teste exato de Fisher. Coleta de sangue e urina para determinações de marcadores metabólicos foi feita em 62 indivíduos e as médias dos valores foram comparados à distribuição alélica e genotípica do rs1544410. Não houve associação entre alelos ou genótipos dos polimorfismos rs1801131 e rs1801133 com RD. O alelo b e o grupo genotípico Bb+bb do rs1544410 foram mais frequentes no grupo de afetados apresentando leve significância: [OR 0.5 (95% IC 0.31-0.98) p=0,0478] e [OR 3.4 (95% IC 1.07-10.9) p=0,496] respectivamente. Nenhuma das variáveis clínicas estiveram associadas com rs1544410 embora uma tendência para valores maiores de proteína C-reativa em portadores do alelo b tenha sido identificada mas sem significância estatística. Em conclusão este estudo sugere que na amostra estudada o polimorfismo rs1544410 do VDR esteve relacionado ao risco de RD, mas não o rs1801131 e rs1801133 do MTHFR. Palavras-chave: diabetes mellitus tipo 2; MTHFR; retinopatia diabética; VDR.

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Fragoso, Thiago Sotero. "Lupus Eritematoso Sistêmico e sua associação com polimorfismos dos genes codificante do receptor da vitamina D (VDR) e antígeno leucocitário humano G (HLA-G)." Universidade Federal de Pernambuco, 2014. https://repositorio.ufpe.br/handle/123456789/11893.

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O Lúpus Eritematoso Sistêmico (LES) é uma doença autoimune multissistêmica. Fatores genéticos podem aumentar o risco de desenvolver o LES, contribuindo com a quebra da auto-tolerância e desenvolvimento de autoanticorpos patogênicos. Vários genes já foram associados à susceptibilidade ao LES, entre eles os que codificam o Antígeno Leucocitário Humano e as proteínas envolvidas na imunomodulação. Recentemente, o papel imunorregulador da vitamina D, realizado através da sua ligação com seu receptor (VDR) tem ganhado destaque. Outrossim, o Antígeno Leucocitário Humano G (HLA-G) tem demonstrado importante função no mecanismo de tolerância imunológica. Sendo assim, a hipótese deste trabalho é de que polimorfismos genéticos do VDR e HLA-G estejam associados à susceptibilidade ao desenvolvimento de manifestações clínicas no LES. Neste sentido, foram desenvolvidos três estudos de caso-controle envolvendo 128 pacientes com LES de Recife/PE e 158 de Ribeirão Preto/SP. Cinco TagSNPs para o gene VDR e 25 SNPs do gene HLA-G foram avaliados através de genotipagem, além de uma meta-análise envolvendo a inserção/deleção (ins/del) de 14pb do HLA-G. Foi verificada associação com a susceptibilidade ao LES, na população do Recife/PE, com os SNPS rs11168268 e rs2248098 do VDR, e com o SNP rs1707 do HLA-G. Ainda, o haplótipo TCGITCCCGAG do HLA-G foi associado ao desenvolvimento do LES. Em relação às manifestações clínicas, 3 dos 5 SNPs testados para o VDR (rs11168268, rs2248098 e rs1540339) foram associados ao risco de desenvolvimento de nefrite na população de Recife/PE. Na população de Ribeirão Preto-SP foram observadas associações com alterações cutâneas (rs11168268), alterações imunológicas (rs2248098), artrite (rs3890733) e produção de anticorpos anti-DNA (rs4760648). Em relação ao HLA-G, estudado na população de Recife/PE, foram observadas associações com lesões cutâneas (-725 C>G>T), alterações imunológicas (-400 G>A e -391 G>A), manifestações hematológicas (alelo mutante em homozigoze na posição -762 C>T) e artrite (insG540). A meta-análise demonstrou associação do LES com a inserção/deleção de 14pb do gene HLA-G. Dessa forma, no presente trabalho podemos concluir que os genes HLA-G e VDR estavam associados ao LES e/ou às suas manifestações clínicas nas populações estudadas, podendo influenciar no desenvolvimento da doença.

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Zylbersztejn, Florence. "Etude du rôle du récepteur à la vitamine D (VDR) dans l'hématopoïèse normale et dans les Leucémies Aiguës Myéloïde -lien avec la voie des Bone Morphogenetic Protein." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS480.

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Une des causes d’échec les plus importantes dans la prise en charge des cancers est la rechute, reflet de la persistance de cellules souches cancéreuses. Les leucémies aiguës myéloïdes représentent la forme principale de leucémie aiguë chez l’adulte et sont caractérisées par une prolifération excessive de cellules immatures et un défaut d’apoptose. En haut de la hiérarchie clonale, les cellules souches leucémiques (CSL) au travers de leurs capacités fonctionnelles participent à l’initiation et la maintenance de la maladie. Ces cellules sont régulées à la fois de façon extrinsèque au travers du microenvironnement et de façon intrinsèque notamment les facteurs de transcription.Notre équipe travaille sur le récepteur à la vitamine D (VDR) et son ligand la vitamine D (VD) et a mis en évidence une synergie d’action entre chélation martiale et VD afin de lever le blocage de différenciation des LAM avec une toxicité réduite (Callens et al, JEM 2010). Une étude clinique rétrospective a été conduite mettant en évidence qu’un taux de vitamine D élevé chez les patients atteints de LAM avant tout traitement leur confère un meilleur pronostic (Paubelle, Zylbersztejn et al, Plos One 2013) . Nous poursuivons donc ce projet sur l’étude la voie VD/VDR dans la maintenance des cellules souches hématopoïétiques et sa dérégulation dans la LAM. Mon projet doctoral a pour objectif de déterminer l’implication du microenvironnement tumoral (voie des BMP et du VDR) dans le maintien des cellules souches leucémiques de LAM. Notre hypothèse de travail est que le récepteur à la vitamine D en plus de son rôle différenciant connu, aurait un impact sur le maintien des cellules souches hématopoïétiques normales et de LAM et que son mécanisme d’action passerait par la voie des Bone Morphogenetic Protein. Nous avons dans un premier temps démontré l’importance du VDR dans la régulation des CSH et pu tester l’intérêt de l’emploi de son ligand afin de cibler spécifiquement les cellules souches leucémiques dans des modèles pré-cliniques. Enfin nous avons pu confirmer la dérégulation de cette voie dans des cellules primaires de LAM et la régulation de ce récepteur par la voie des Bone Morphogenetic Protein. Ces travaux ouvrent de nouvelles perspectives dans la compréhension dans la biologie des CSH et de leur dérégulation dans la LAM
One of the most important causes of failure in the management of cancer is relapse, due to cancer stem cells persistence. Acute Myeloid Leukemias (AML) are the major form of acute leukemia in adults and are characterized by excessive proliferation of immature cells and apoptosis defect. At the top of the clonal hierarchy, leukemic stem cells (LSC) through their functional abilities participate in the initiation and maintenance of the disease. These cells are regulated both extrinsically mechanisms through the microenvironment and intrinsically by transcription factors.Our team is working on the Vitamin D Receptor (VDR) and its ligand Vitamin D (VD) and has demonstrated a synergistic action between iron chelation and VD in order to lift the differentiation blocking of AML with reduced toxicity (Callens et al, JEM 2010). A retrospective clinical study was conducted showing that a high vitamin D level in patients with AML before any treatment gives them a better prognosis (Paubelle, Zylbersztejn et al, Plos One 2013). We are continuing this project on the study of the VD/VDR pathway in the maintenance of hematopoietic stem cells (HSC) and its deregulation in AML. My project aims to determine the involvement of the tumor microenvironment (BMP and VDR pathway) in the maintenance of AML-LSC. Our working hypothesis is that the vitamin D receptor, in addition to its known differentiating role, would have an impact on the maintenance of normal HSC and AML and that its mechanism of action would be through the Bone Morphogenetic Protein pathway. We first demonstrated the importance of VDR in the regulation of HSCs and tested the interest of the use of its ligand to specifically target LSC in pre-clinical models. Finally we were able to confirm the deregulation of this pathway in primary AML cells and the regulation of this receptor by the Bone Morphogenetic Protein pathway. These works open up new perspectives in the understanding in CSH biology and their deregulation in AML

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Dantas, Vanessa de Melo Cavalcanti. "Análise da influência dos polimorfismos rs2228570 e rs1544410 do gene vdr na ocorrência de fissuras labiopalatinas não sindrômicas." Universidade Federal da Paraíba, 2017. http://tede.biblioteca.ufpb.br:8080/handle/tede/9819.

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The cleft lip and palate can be classified according to the affected structures in CL, CP or CLP (combination of both), can be classified into syndromic or non-syndromic fissures, presenting several risk factors. Vitamin D is considered a steroid hormone of great importance because it is involved in fundamental physiological processes. Vitamin D insufficiency is associated with several complications in pregnancy including pre-eclampsia and premature birth, suggesting an important role of this vitamin in maintaining pregnancy and fetal development. The VDR gene is located on the long arm of chromosome 12 and more than 470 polymorphisms were identified in the human VDR gene, among them rs2228570 and rs1544410. The objective of this work was to determine the allelic and genotypic frequencies and the associations of rs2228570 and rs1544410 with the susceptibility for the development of CL/P and CP. A control case study was used, involving 127 double tests of patients attended by the Lauro Wanderley University Hospital, being 74 CL/P and 53 CP with their respective mothers, and 82 healthy doublets attended at the Hospital Cândida Vargas. Genomic DNA from children and mothers was obtained from oral mucosal cells. The genotypes were identified by the Restriction Fragment Length technique (PCR-RFLP) and analyzed using the chi-square test. The difference of the mean age of the mothers presented difference between the control group and the CP group. The percentage of fissured children who presented a family history of clefts compared to control presented significance (p = 0.0001). The genotypic distribution and allelic frequency of rs2228570 in mothers groups and the affected groups was not different from the control group. For the rs1544410 polymorphism the comparison between the children of the CP and control groups showed a significant difference in the genotypic distribution (p = 0.017) and allele frequency presented (p = 0.008) with a predominance of the b allele in the FP group. No significant differences were found for genotypes and allelic frequency of rs1544410 in the mother group. The results of this study suggest that the b allele of rs1544410 may act as a risk factor for development and that the BB genotype may act as a protective factor for CP.
As fissuras labiopalatinas podem ser classificadas, com base nas estruturas afetadas, em fissura labial (FL), fissura palatina (FP) e fissura labiopalatina (FLP), todas podendo constituir anomalias sindrômicas ou não-sindrômicas, apresentando vários fatores de risco. A vitamina D é considerado um hormônio esteróide de grande importância por estar envolvido em processos fisiológicos fundamentais. A insuficiência de vitamina D está associada a várias complicações na gravidez incluindo pré-eclâmpsia e nascimento prematuro, sugerindo um papel importante desta vitamina na manutenção da gravidez e desenvolvimento fetal. O gene VDR está localizado no braço longo do cromossomo 12 e mais de 470 polimorfismos foram identificados no gene VDR humano, dentre eles o rs2228570 e rs1544410. O objetivo deste trabalho foi determinar as frequências alélicas e genotípicas e as associações de rs2228570 e rs1544410 com a suscetibilidade para o desenvolvimento de FL/P e FP. Foi desenvolvido um estudo de caso controle, envolvendo 127 duplas de pacientes atendidos no Serviço de Fissurados do Hospital Universitário Lauro Wanderley, sendo 74 FL/P e 53 FP com suas respectivas genitoras, e 82 duplas de crianças e genitoras saudáveis atendidas no Hospital Cândida Vargas. O DNA genômico de crianças e genitoras foi obtido a partir de células de mucosa oral. Os genótipos foram identificados pela técnica de Comprimento de Fragmentos de Restrição (PCR-RFLP) e analisados utilizando o teste qui-quadrado. A diferença da idade média das mães apresentou diferença entre grupo controle e grupo FP. A porcentagem de filhos fissurados que apresentaram ter histórico familiar de fissuras comparado ao controle apresentou significância (p= 0,0001). A distribuição genotípica e frequência alélica de rs2228570 tanto no grupo de genitoras quanto de afetados não foi diferente do grupo controle. Para o polimorfismo rs1544410 a comparação entre crianças do grupo FP e controle mostrou diferença significativa na distribuição genotípica (p = 0,017) e frequência alélicas apresentou (p= 0,008) com predominância do alelo b no grupo FP. Não foram encontradas diferenças significantes para os genótipos e frequência alélica de rs1544410 no grupo de genitoras. Os resultados deste estudo sugerem que o alelo b do rs1544410 pode atuar como fator de risco de desenvolvimento e que o genótipo BB pode atuar como fator protetor para FP.

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Souza, Cleber Machado de. "Análise da associação entre polimorfismos no gene do receptor da vitamina D (VDR) e a suscetibilidade à doença renal crônica e à doença periodontal = Association between vitamin d receptor gene polymorphisms and susceptibility to chronic kidney disease and periodontitis / Cleber Machado de Souza ; orientadora, Paula Cristina Trevilatto ; co-orientador, Roberto Pecoits-Filho." reponame:Biblioteca Digital de Teses e Dissertações da PUC_PR, 2007. http://www.biblioteca.pucpr.br/tede/tde_busca/arquivo.php?codArquivo=1256.

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Tese (doutorado) - Pontifícia Universidade Católica do Paraná, Curitiba, 2007
Inclui bibliografias
A doença renal crônica (DRC) e a doença periodontal (DP) são sérios problemas de saúde-pública, sendo esta última especialmente negligenciada na população de renais crônicos. A vitamina D é um hormônio esteróide solúvel, metabolizado no fígado e nos rins,
Chronic kidney disease (CKD) and periodontitis (PD) are serious public-health concerns, but the latter has been especially neglected in the CKD population. Vitamin D is a fat-soluble steroid hormone, metabolized in the liver and then in the kidney, result

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ALVES, Neyla Maria Pereira. "Influência de polimorfismos de base única (SNPs) no gene do receptor de vitamina D (VDR) na resposta à Terapia Antirretroviral (TARV) de pessoas vivendo com Vírus da Imunodeficiência Humana tipo 1 (HIV-1)." Universidade Federal de Pernambuco, 2015. https://repositorio.ufpe.br/handle/123456789/16120.

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CAPES
CNPq
HIV/aids (Vírus da Imunodeficiência Humana/aids) é considerado uma pandemia, envolvendo mais de 70 milhões de infecções e 35 milhões de mortes desde o primeiro relato na década de 80. O HIV tipo 1 (HIV-1) infecta principalmente linfócitos T CD4+ e linhagens de macrófagos, tendo sua patogenicidade definida pela depleção de LT CD4+. Além disso, a condição de infecção por HIV-1 é bastante complexa e dependente de diversos fatores relacionados à variabilidade dos indivíduos no que diz respeito à suscetibilidade à infecção e à progressão para a aids, sendo observada a ativação imunológica generalizada. Envolvida na modulação das respostas imunes inata e adaptativa encontra-se a vitamina D, que desempenha papel no metabolismo mineral e apresenta efeito pleiotrópico no crescimento e diferenciação celulares. Seus efeitos imunológicos são dados a partir da ligação com o receptor de vitamina D (VDR) de diversas células, regulando a liberação de citocinas, a função e proliferação de linfócitos T e a produção de peptídeos antimicrobianos como a catelicidina. O VDR atua modulando a ação dessa vitamina induzindo a resposta imune local e variações genéticas presentes no gene codificador do VDR podem levar à diminuição de sua atividade e, consequentemente, ao prejuízo para o papel da vitamina D. Nos indivíduos infectados pelo HIV, os níveis de deficiência dessa vitamina são altos e fatores como raça, insuficiência renal, pouca exposição à luz ultravioleta e exposição as drogas anti-HIV, como o Efavirenz, estão associados a essa deficiência, respectivamente, sendo determinantes para a susceptibilidade à infecção pelo HIV e a predição da progressão da doença. Sendo assim, neste trabalho foram estudados seis polimorfismos de base única (SNPs) (rs3890733, rs476048, rs1540339, rs2248098, rs2228570 e rs11568820) presentes no gene do receptor de vitamina D (VDR) e sua influência na resposta dos pacientes à Terapia Antirretroviral (TARV). Foram recrutados 107 pacientes acompanhados e tratados no Hospital Dia do Instituto de Medicina Integral Professor Fernando Figueira (IMIP), subdivididos em quatro grupos: I- Sucesso Terapêutico, II- Falha Terapêutica, III- Sucesso Imunológico, IV- Falha Imunológica, e analisadas variáveis clínicas e epidemiológicas, como gênero, idade, peso e etnia. Não foram observadas associações estatísticas nas análises isoladas entre os polimorfismos dos genes do VDR com a falha virológica ou a resposta imunológica. Porém, nas análises multivariadas, o genótipo C/C do rs1540339 mostrou-se associado com o gênero no sucesso virológico (OR=0,08, p=0,04). Em adição, a análise envolvendo peso, etnia e gênero e o rs3890733 mostrou associação com a resposta imunológica para os genótipos C/C e T/T no modelo sobredominante (OR=0,21, p=0,024). Os resultados indicam a importância do receptor de vitamina D em infecções por HIV-1 e poderão contribuir para o entendimento da variabilidade das respostas dos pacientes à TARV.
HIV/aids (Human Immunodeficiency Virus/aids) is considered a pandemic, involving more than 70 million infections and 35 million deaths since the first report in the 80’s. HIV type 1 (HIV-1) infects mainly T lymphocytes CD4 + and macrophage lineages, and their pathogenicity is defined by the depletion of CD4 +. Furthermore, the condition of HIV- 1 infection is very complex and dependent on many factors related to the individual variability, regarding the susceptibility to infection and progression to AIDS, generalized immune activation being observed. Involved in the modulation of innate and adaptive immune responses is vitamin D, which plays a role in mineral metabolism and has pleiotropic effects on cell growth and differentiation. Their immune effects are data from binding to the vitamin D receptor (VDR) in various cells, regulating the release of cytokines, the function and proliferation of T lymphocytes and the production of antimicrobial peptides as cathelicidin. The VDR acts modulating the action of vitamin D by inducing local immune responses and genetic variations present in the VDR encoding gene can lead to reduction of its activity and consequently, disfunction in the role of vitamin D. In HIV-infected individuals, this vitamin deficiency levels are high and factors such as race, kidney failure, lower exposure to ultraviolet light and exposure to anti- HIV drugs, such as Efavirenz, are associated with this deficiency, being determinants on the susceptibility to HIV infection as well as prediction of disease progression. Therefore, in this work we studied six single nucleotide polymorphisms (SNPs) (rs3890733, rs476048, rs1540339, rs2248098, rs2228570 and rs11568820) present in the D vitamin receptor gene (VDR) and its influence on patients’ response to Antiretroviral Therapy (ART). We recruited 107 patients followed from the Hospital Day Integrative Medicine Institute Professor Fernando Figueira (IMIP), subdivided into four groups: I. Therapeutic Success, II. Therapeutic Failure, III. Immune Success, IV. Immune Failure, and analyzed clinical and epidemiological variables, such as gender, age, weight and ethnicity. No statistically significant associations were observed in the isolated analyzes between polymorphisms of the VDR gene with therapeutic failure or immune response. However, in multivariate analyzes, the rs1540339 C/C genotype was associated with gender in therapeutic success (OR = 0.08, p = 0.04). In addition, analysis involving weight, ethnicity and gender and the rs3890733 showed association with the immune response to the C/C genotype and T/T in overdominant model (OR = 0.21, p = 0.024). The results indicate the importance of vitamin D receptor in HIV- 1 infections and may contribute to the understanding of variability of patient’s various responses to ART.

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Filho, Victor Celso Nogueira Fonseca. "Influência da vitamina D por via intratumoral na proliferação e expressão de genes alvo de xenoenxerto de câncer de mama de pacientes pós-menopausadas." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-13012014-121103/.

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O efeito antiproliferativo do calcitriol foi detectado principalmente em linhagens de carcinoma mamário expostas in vitro a alta concentração hormonal (10 - 100nM), que é associado com hipercalcemia em seres humanos. Nossa hipótese era que a administração intratumoral de calcitriol permitiria maior concentração do hormônio e ativação da via genômica. Para testar esta hipótese, um modelo de enxerto tumoral que reproduz o mais próximo das características moleculares do tumor primário, foi estabelecida. As amostras de câncer de mama recolhidos foram enxertados em camundongos nude e depois da sexta semana, semana, os enxertos tumorais foram tratados semanalmente com injeções intra-tumorais de veículo (controle) ou o calcitriol 0,06 mcg (dose que pode permitir que picos séricos de calcitriol na faixa terapêutica prevista) durante seis semanas. A proliferação e apoptose do enxerto tumoral Veículo (controlo) ou o calcitriol 0,06 mcg (dose que pode permitir que o soro de pico, assim como, a expressão dos genes alvos foram avaliadas através de reações imunohistoquímica ou RT-PCR. A expressão de VDR foi detectada em todas as amostras, assim como uma tendência para maior expressão de mRNA CYP24A1 (indução 10-18 vezes) em amostras tratadas com calcitriol, indicando que a via genómica foi induzida pelo hormonio. O elevado índice proliferativo, avaliado pela expressão de Ki67, foi detectado. No entanto, não havia diferenças na expressão de marcadores de proliferação (incorporação de BrdU, Ki67 e CDKN1B expressão) nem marcadores de apoptose (caspase-3 clivada e BCL2 expressão) entre os enxertos tumorais tratados por veículo e calcitriol tratado. Além disso, não houve diferença entre os grupos detectada na expressão de mRNA do CDKN1A. Em resumo, os efeitos antitumorais não foram observados neste modelo de enxerto tumoral. A indução do gene alvo CYP24A1 pode ter em parte impedido os efeito antitumorais da vitamina D
Antiproliferative effects of calcitriol were mainly detected in breast carcinoma lineages exposed in vitro to high hormone concentrations (10-100 nM), which is associated with hypercalcemia in human beings. Our hypothesis was that intra-tumoral administration of calcitriol would allow higher issue concentration of the hormone and activation of the genomic pathway. To test this hypothesis, a tumorgraft model, that more closely reproduces the molecular characteristics of the primary tumor, was established. Freshly collected breast cancer samples were grafted in nude mice and after the 6th week, tumorgrafts were treated weekly with intra-tumoral injections of vehicle (control) or calcitriol 0.06 mcg (dose that may allow peak serum calcitriol levels in the predicted therapeutic range) for six weeks. Tumorgraft proliferation and apoptosis, as well as expression of target genes, were evaluated through immnunohistochemistry reactions or RT-PCR. VDR expression was detected in all samples as well as a trend towards higher expression of CYP24A1 mRNA (10-18 fold induction) in calcitriol treated samples, indicating that the genomic pathway was induced by the hormone. A high proliferative index, evaluated by Ki67 expression, was detected. However, there were neither differences in the expression of proliferation markers (BrdU incorporation, Ki67 and CDKN1B expression) nor in apoptosis markers (cleaved caspase 3 and BCL2 expression) between vehicle and calcitriol treated tumorgrafts. In addition, no difference between groups was detected for the expression of CDKN1A mRNA. In summary, calcitriol antitumoral effects were not observed in this tumorgraft model. Calcitriol induction of the target gene CYP24A1, might have in part, precluded vitamin D antitumoral effects

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23

Whitlatch, Andrew J. "p63 and VDR are regulated by Vitamin D (VD3) and UV signaling." Wright State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=wright1278540370.

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24

Lowe, Lorraine Claire. "Vitamin D and the vitamin D receptor in breast cancer." Thesis, St George's, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428038.

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25

Singer, Jonathan A. "Vitamin D and Chronic Pain: A Comprehensive Review." Master's thesis, Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/216559.

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Oral Biology
M.S.
In recent years vitamin D has gained popularity in the media, on the internet, and throughout alternative treatment practitioners as a cheap and effective option to treat many diseases. Research showing that vitamin D receptors are present in virtually all cells of the body, and the increasing data demonstrating a relationship of vitamin D metabolites to chronic diseases, have led to widespread treatment of medical conditions with vitamin D supplementation. Chronic pain and inflammatory conditions are increasingly linked to vitamin D deficiency. The question posed in this review is whether there is significant, quality research to recommend vitamin D supplementation for patients with chronic pain conditions. Utilizing publications from PubMed for the review, various search terms were entered for vitamin D (vitamin D; vitamin D2; vitamin D3; 1,25-dihydroxyvitamin D3; 1,25-dihydroxycholecalciferol; 25 hydroxycholecalciferol; 25-hydroxyvitamin D; alfacalcidol; calcidiol; calcitriol; calcifediol; calciferol; ergocalciferal; cholecalciferol); and "pain." The search was continued from the last day of the Straub et. al. review, September 8th, 2008. The last search was conducted on December 5, 2012. The search protocol from Straub et. al was followed as well. Also, added to this search protocol were the terms: vitamin D receptor; VDR and "pain." These terms enabled a search for genetic links between vitamin D and pain. The search criteria resulted in nine relevant articles (from the original 1,069 studies) with varying treatment protocols in each article making any statistical representation impossible. Results on the effectiveness of vitamin D correlation with chronic pain were extremely variable, with most papers drawing the conclusion that more quality research needs to be implemented on the subject. Due to the variability and lack of quality randomized controlled trials, the current literature can only suggest a possible link between vitamin D levels and pain. Also, recent research into Vitamin D Receptors (VDR) has opened up a possible connection between VDR polymorphisms and pain. So, after a comprehensive review of vitamin D, Vitamin D Receptors, and pain, there is still not enough evidence to recommend supplementation to treat chronic pain conditions. However, enough evidence is available to recommend future high quality, randomized controlled trials to help determine the influence vitamin D and VDRs have on pain issues.
Temple University--Theses

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26

Quarni, Waise. "VDR-RIPK1 Interaction and its Implications in Cell Death and Cancer Intervention." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6569.

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Receptor interacting protein kinase 1 (RIPK1) is an enzyme acting downstream of tumor necrosis factor alpha to control cell survival and death. RIPK1 expression has been reported to cause drug resistance in cancer cells; but so far, no published studies have investigated the role of RIPK1 in vitamin D action. In the present study, we investigated whether RIPK1 played any role in 1,25-dihydroxyvitamin D3 (1,25D3)-induced growth suppression. In our studies, RIPK1 decreased the transcriptional activity of vitamin D receptor (VDR) in luciferase reporter assays independently of its kinase activity, suggesting a negative role of RIPK1 in 1,25D3 action. RIPK1 also formed a complex with VDR and deletion analyses mapped the RIPK1 binding region to the C-terminal ligand-binding domain of VDR. Subcellular fractionation analyses indicated that RIPK1 increased VDR retention in the cytoplasm, which may account for the inhibition of VDR transcriptional activity. Consistent with the reporter analyses, 1,25D3-induced growth suppression was more pronounced in RIPK1-null mouse embryonic fibroblasts (MEF) and RIPK1 knockdown ovarian cancer cells than control cells. We have also shown that VDR was involved in RIPK1-mediated cell death pathway in a cell line specific manner. In vivo study showed that VDR deletion delayed the necroptotic response to tumor necrosis factor alpha in mice. Western blot analyses of platinum sensitive and resistant cell lines showed a correlation between RIPK1 expression and drug resistance, suggesting a possible role of RIPK1 in drug resistance. In conclusion, this study is the first to define RIPK1 as a VDR repressor, projecting RIPK1 depletion as a potential strategy to increase the potency of 1,25D3 and its analogs for cancer intervention.

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27

Bueno, Larissa Souza Mario. "Vitamina D, polimorfismos do gene VDR e neurofibromatose 1." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/52955.

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Introdução: A Neurofibromatose tipo 1 (NF1) é uma doença genética autossômica dominante causada por mutação no gene NF1 (17q11.2; proteína neurofibromina). A incidência é de aproximadamente 1:3500 recém-nascidos e o diagnóstico clínico é possível na maioria dos casos. Alguns estudos sugeriram que pacientes com NF1 são mais suscetíveis a apresentar deficiência de vitamina D quando comparados à população geral. Objetivo: Determinar os níveis de 25(OH)D em indivíduos com NF1 e em controles saudáveis. Nos pacientes com NF1 nos também avaliamos o fenótipo clínico e analisamos polimorfismos comuns do gene VDR (BsmI e FokI) para avaliar se estavam correlacionados com os níveis de 25(OH)D. Métodos: Estudo de caso-controle que incluiu 45 pacientes com NF1 do Sul do Brasil e 45 controles saudáveis pareados por idade, sexo e tipo de pele de acordo com a classificação de Fitzpatrick. Resultados e Conclusões: Setenta e sete vírgula oito por cento dos 90 sujeitos de pesquisa apresentaram níveis de 25(OH)D abaixo de 30ng/ml. Deficiência de 25(OH)D (<20ng/mL) foi observada em 28 (31,1%) e insuficiência (de 20 a 30ng/mL) em 42 (46,6%). Deficiência ou insuficiência de 25(OH)D não foi mais frequente em pacientes com NF1 do que em controles (p=0,074). Nos não observamos qualquer associação entre os polimorfismos do gene VDR e os níveis de vitamina D sugerindo que o fenótipo da insuficiência ou deficiência bioquímica de 25(OH)D nos pacientes estudados não está associado com essas variantes genéticas.
Introduction: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene (17q11.2, neurofibromin). The estimated incidence is approximately 1:3500 newborns and clinical diagnosis is possible in the majority cases. A few studies suggest that patients with NF1 are more likely to have vitamin D deficiency when compared to the general population. Objectives: The goal of the study was to determine the levels of 25-OH-vitamin D [25(OH)D] in individuals with NF1 and disease-unaffected controls. In NF1 patients we also assessed clinical phenotype and analyzed common VDR gene polymorphisms (BsmI and FokI) to verify whether they were associated with lower vitamin D levels. Methods: Case-control study that included 45 NF1 patients from Southern Brazil and 45 healthy controls matched by sex, skin type and age to the cases. Results and conclusions: Overall, 70 (77.8%) of the individuals studied had levels of 25(OH)D below 30ng/ml: vitamin D deficiency was observed in 28 (31.1%) and vitamin D insufficiency in 42 (46.6%) subjects. 25(OH)D deficiency or insufficiency were not more frequent in NF1 patients than in controls (p=0,074). We did not observe an association of VDR gene polymorphisms and vitamin D levels suggesting that the insufficient or deficient biochemical phenotypes in the patients studied here are not associated with these genetic variants.

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28

Correa, Pamela. "Vitamin D and its receptor in parathyroid tumors." Doctoral thesis, Uppsala University, Department of Surgical Sciences, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2684.

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Correa, P. 2002. Vitamin D and its receptor in parathyroid tumors. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1186. 49 pp. Uppsala. ISBN 91-554-541-0

Hyperparathyroidism (HPT) is characterized by tumor development in the parathyroid glands and excessive production of parathyroid hormone. Parathyroidectomy is the only considered therapy for the majority of patients.

LOH (loss of heterozygosity) analysis revealed putative tumor suppressor genes on chromosome regions 1p and 11q in tumors from patients with truly mild hypercalcemia.

Active vitamin D [1,25(OH)2D3] and its receptors, the vitamin D receptor (VDR), are essential regulators of the calcium homeostasis and are involved in HPT development. The VDR-FokI polymorphism, coupled to bone mineral density, was found not to be associated to development of primary HPT (pHPT). The total VDR mRNA levels is reduced in adenomas of pHPT as well as in hyperplastic glands of secondary HPT (sHPT). The VDR exon 1f transcripts were exclusively downregulated in the adenomas of pHPT, suggesting default regulation of the tissue-specially expressed VDR 1f promoter. The cytochrome P450 enzymes responsible for synthesis and degradation of 1,25(OH)2D3, namely vitamin D3 25-hydroxylase (25-hydroxylase), 25-hydroxyvitamin D3 1a-hydroxylase (1a-hydroxylase) and 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) were found to be expressed in normal and pathological parathyroid glands. Tumors of pHPT and sHPT demonstrated increased 1a-hydroxylase and reduced 24- and 25-hydroxylase expression, suggesting an augmented local production of active vitamin D. In contrast, parathyroid carcinomas displayed reduced expression of all three hydroxylases. The gained knowledge of vitamin D metabolism and catabolism in parathyroid tumors may indicate possibilities for novel treatment of sHPT and perhaps pHPT.

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29

Torkko, Kathleen Carroll. "Vitamin D receptor gene polymorphisms and prostate cancer /." Connect to full text via ProQuest. IP filtered, 2005.

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Thesis (Ph.D. in Epidemiology) -- University of Colorado at Denver and Health Sciences Center, 2005.
Typescript. Includes bibliographical references (leaves 95-118). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

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30

Zhang, Xueming. "Vitamin D receptor deficiency and postnatal tooth formation." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. http://www.mhsl.uab.edu/dt/2007m/zhang.pdf.

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31

Kim, Han S. "Sunlight, vitamin D receptor polymorphisms, and colorectal cancer /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/10862.

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32

Van, Pelt Chad. "The Interaction of β-catenin, Vitamin D, Resveratrol, and Two Common VDR Polymorphic Variants in Colorectal Carcinogenesis." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/606228.

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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
Vitamin D and resveratrol have been widely researched in recent years, especially their apparent abilities to impact a host of physiological processes. Resveratrol, a phytoalexin found in various berries, peanuts, and other vegetables, is purported to possess anti-aging, anti-inflammatory, antioxidant, anticancer, neuroprotective, and antiarthritic properties, while the classical endocrine functions of vitamin D are the control of calcium and phosphate homeostasis. The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is typically synthesized in the kidney, bound to vitamin D binding protein, and shuttled to cellular target sites. Mounting data on the effect of locally synthesized 1,25D in immune, epithelial, neural, and other tissues have led to an increased awareness of the myriad functions of vitamin D, including detoxification, cellular aging and its modulation, immune regulation, neurotransmitter activity, and metabolic control. Both endocrine and intracrine actions of vitamin D are mediated by the vitamin D receptor (VDR), a nuclear receptor that controls vitamin D-directed transcription of target genes. Importantly, the VDR has numerous polymorphisms, one of which results in two phenotypically distinct isoforms, designated M1 and M4. VDR M4 is postulated to be more active than M1 in vitamin D-dependent transactivation. Variable binding affinities between the two isoforms and VDR interacting proteins such as TFIIB and RXR have also been observed. Another protein known to interact with VDR is β-catenin, the mediator of the Wnt/β-catenin signaling pathway that can drive colorectal carcinogenesis. The goal of this study was to investigate the ability of vitamin D and resveratrol to regulate the Wnt/β-catenin system via stimulation of β-catenin-VDR (both M1 and M4) interaction and subsequent inhibition of β-catenin-mediated transcription. The current data reported herein support and extend previous work by demonstrating that VDR binds directly to β-catenin and that both vitamin D and resveratrol appear to enhance this interaction. We also present data that 1,25D-stimulated VDR is capable of inhibiting β-catenin transcriptional activity. Significantly, we have shown that the two common VDR polymorphisms M1 and M4, are functionally variable, both in their induction of vitamin D-dependent genes and in their inhibition of β-catenin-mediated transcription. VDR M4 exhibits both elevated transactivation and amplified capacity for β-catenin suppression compared to M1, and studies employing site-directed mutagenesis of VDR implicate the glutamic acid at position 2 as being responsible for the reduced activity of the M1 variant. Both polymorphic VDR variants display 1,25D-mediated enhancement of -catenin association, with the M1 SNP possessing a lower basal (-1,25D) binding to this protein partner but a higher fold stimulation in -catenin interaction in the presence of 1,25D. Taken together, these data support the notions that VDR influences pathways important for colorectal carcinoma (CRC) development, and that supplementation with vitamin D and resveratrol may reduce colon cancer risk in the general population, especially in individuals with the less active M1 VDR polymorphism. A comprehensive understanding of 1,25D and resveratrol action in VDR signaling may allow for a more personalized approach toward treating vitamin D–related disorders and evaluating risk for carcinogenesis.

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33

Köstner, Kim Karola [Verfasser], and Jörg [Akademischer Betreuer] Reichrath. "Genetische Varianten des Vitamin D Rezeptors (VDR) bei kutanen Plattenepithelkarzinomen und Basalzellkarzinomen / Kim Karola Köstner. Betreuer: Jörg Reichrath." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2011. http://d-nb.info/1051405556/34.

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34

ALLEGRETTO, ELIZABETH ANNE. "STRUCTURE - FUNCTION RELATIONSHIPS OF THE VITAMIN D HORMONE RECEPTOR." Diss., The University of Arizona, 1987. http://hdl.handle.net/10150/184182.

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Avian intestinal cytosoluble receptors for 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) were subjected to limited trypsin digestion, endogenous proteolytic action, as well as carboxypeptidase treatment, and the physical and functional properties of the resulting discrete polypeptide fragments were identified and contrasted with the native 1,25(OH)₂D₃ receptor. Resultant fragments were followed by tracing either radioactive 1,25(OH)₂D₃ or by probing with anti-receptor monoclonal antibodies. Two differentially trypsin-sensitive effects on the 1,25(OH)₂D₃ receptor were noted when fragments were detected by their ability to bind 1,25(OH)₂[³H]D₃. Two hormone-bound fragments of 40 and 30 kDa were formed; neither bound to DNA-cellulose nor anti-receptor monoclonal antibodies. Immunoblot technology was used to show the disappearance of the 60 kDa receptor with increasing trypsin concentrations, paralleling the appearance of an immunoreactive 20 kDa fragment. The 20 kDa fragment did not bind hormone but was capable of interacting with DNA-cellulose in a fashion identical to that of the 60 kDa receptor. This fragment is likely the complementary fragment to the hormone-bound fragment of 40 kDa that is described above. In contrast to the exogeneous effect of trypsin, incubation of chick intestinal cytosol resulted in the time-dependent formation of an endogenous protease-derived fragment of 45 kDa. This species retained the hormone-binding site and the antibody determinant, but was devoid of DNA-binding activity. Moreover, it did not generate the trypsin-dependent 20 kDa fragment and therefore was derived from the opposite end of the receptor molecule. Carboxypeptidase treatment of the 1,25(OH)₂D₃ receptor produces a 56 kDa fragment which does not retain hormone, but which does bind to DNA-cellulose and monoclonal antibody. These combined data from various limited enzymatic cleavage studies of the receptor have facilitated the construction of a schematic model of the chick receptor in which the immunoreactive epitope is located between the N-terminal DNA-binding domain and the C-terminal hormone-binding domain. This map for the 1,25(OH)₂D₃ receptor protein is consistent with the general structure of steroid and thyroid hormone receptors and places the vitamin D hormone receptor in a class of macromolecules that are postulated to bind enhancer regions of responsive DNA and thereby control target gene transcription.

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35

Banwell, Claire. "Vitamin D receptor signalling is disrupted in breast cancer." Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433504.

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36

Pyburn, Jaeden, and Matthew Keasey. "Development of PDIA3 and VDR Knockout Human Osteosarcoma SaOs-2 Cells Using CRISPR-Cas9." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/59.

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Intro: Hypovitaminosis D (vitamin D deficiency) has been observed in ageing patients with brain calcification and loss of the vitamin D receptor leads to abnormal calcification of the basal ganglia and thalamus. We have found that vitamin D can reverse calcification of human osteosarcoma SaOs-2 cells in vitro, in apparent contrast to its known effects of increasing bone strength in patients with Rickets and Osteomalacia. Vitamin-D functions through binding to two Vitamin-D responsive proteins; the vitamin D receptor (VDR) and Protein Disulfide isomerase A3 (PDIA3). The aim of this project was to establish VDR and PDIA3 knockout SaOs-2 cells using CRISPR-Cas9 technology. Methods: We designed guide RNA (gRNA) sequences against PDIA3 and VDR using ChopChop, selecting only gRNAs with low predicting non-specific binding probabilities. These gRNA sequences were ordered as oligonucleotides and dimerised before directional cloning into a Cas-9 plasmid. Plasmids were amplified in DH5 E. coli and purified before transfection into SaOs-2 cells together with a plasmid containing the puromycin resistance gene. Cells were treated with puromycin (1 ug/ml) for 4 days to eliminate non-transfected cells. SaOs-2 cells were maintained for 7 days before being passaged and plated for colony selection. Results: Real Time quantitative PCR showed 1 SaOs-2 clone had non-detectable levels of PDIA3 while 4 out of 6 clones had no detectable VDR mRNA relative to wild type cells. Two clones were selected for further analysis. Western blotting of these two clones probing for VDR and PDIA3 confirmed there were no detectable levels of these two proteins. Conclusion: We successfully knocked out expression of the Vitamin-D receptors VDR and PDIA3 in SaOS2 cells. These cells will be used for further study of Vitamin-D related signaling.

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37

MANGELSDORF, DAVID JOHN. "MOLECULAR BIOLOGY AND ACTIONS OF THE VITAMIN-D HORMONE RECEPTOR." Diss., The University of Arizona, 1987. http://hdl.handle.net/10150/184218.

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The active form of vitamin D is the steroid hormone 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. Central to the mechanism of action of 1,25(OH)₂D₃ is its specific, high affinity intracellular receptor. This research focused on the participation of this receptor in the biology, biochemistry, and molecular biology of the vitamin D regulatory system. The effects of 1,25(OH)₂D₃ on the differentiation of hematopoietic cells were investigated using the cultured human promyelocytic leukemia cell line, HL-60, as a model. It was observed that 1,25(OH)₂D₃ induced macrophage differentiation in HL-60 cells and that a direct biochemical correlation existed between 1,25(OH)₂D₃ receptor saturation and a 1,25(OH)₂D₃-stimulated bioresponse. These data implicate 1,25(OH)₂D₃ as a natural cell differentiating agent and the 1,25(OH)₂D₃ receptor as the mediator of this hormone's action. Since the most fundamental level of control occurs by the regulation of gene expression, studies were undertaken to define the transcriptional control by 1,25(OH)₂D₃ over a known vitamin D-regulated endpoint protein. This work resulted in the molecular cloning of cDNAs to two avian intestinal calcium binding proteins, vitamin D-dependent calcium binding protein and a novel calmodulin-like protein. To gain further insight into the role of the 1,25(OH)₂D₃ receptor as a transcriptional regulator, avian and mammalian 1,25(OH)₂D₃ receptor mRNAs were characterized extensively by the techniques of in vitro translation and immunoprecipitation. These mRNAs were then utilized to construct cDNA libraries from which avian and human intestinal 1,25(OH)₂D₃ receptor cDNAs were isolated and their identity verified by hybrid-selected translation, sequencing, and Northern analysis. It was concluded that demonstrated 1,25(OH)₂D₃ receptors are polypeptides of 52-60 kDa whose activity is regulated by 1,25(OH)₂D₃ at both an mRNA and posttranslational level. Furthermore, the deduced amino acid sequence of receptor mRNA included a highly conserved cysteine, lysine, and arginine rich region that is homologous to other steroid receptors and the oncogene product v- erbA. Thus, the vitamin D receptor to be a specific trans -acting factor, modulating the pleiotropic effects of vitamin D including calcium homeostasis, and cellular differentiation.

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38

Gardner, Philip P. "Human vitamin D receptor polymorphisms : a molecular and population analysis." Thesis, University of Warwick, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322482.

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39

Dabbas, Basel. "Combined effects of vitamin D receptor agonists and histone deacetylase inhibition on vitamin D-resistant squamous carcinoma cells." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112395.

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The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), is a key calcium (Ca++) regulatory hormone. It is also associated with functions unrelated to Ca++ homeostasis. Here, special attention is paid towards the anticancer properties of 1,25D. 1,25D strongly inhibits the growth of well-differentiated head and neck squamous cell carcinoma (HNSCC) derived cell lines. However, advanced, less differentiated, HNSCC cell lines (e.g. SCC4) are partially resistant to 1,25D. Resistance to nuclear receptor (NR) agonists is a common event that occurs in other NR-related treatments. For example, some leukemias develop resistance to the usually effective retinoic acid (RA) treatment. However, treating RA-resistant cells with HDAC inhibitors (HDACi) sensitizes them to RA. Thus, this study aims to investigate how treatment with TSA, an HDACi, would affect the response of SCC4 cell lines to 1,25D. We found that TSA had a variety of effects on 1,25D-regulated gene expression. Combined treatment with 1,25D and TSA increased the expression of cell-cycle regulating proteins, but also enhanced the downregulation of key target genes. Given the potential of the 1,25D/HDACi combination in combating cancers, two chimeric compounds, each containing parts of 1,25D and an HDACi, were synthesized in collaboration with Dr. James Gleason (Dept. of Chemistry, McGill). These 1,25D analogs have the HDACi-like structure replacing the 1,25D side chain. Both compounds proved to be agonists of the vitamin D receptor. Moreover, the TSA-substituted compound, called triciferol, effectively induced a-tubulin as well as histones acetylation. This study underlines the potential of combining 1,25D and TSA in cancer treatment, and reveals that bi-functional 1,25D analogs can be produced with potentially enhanced therapeutic activity.

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40

Brady, Heather Lynn. "Vitamin D and the vitamin D receptor gene in children at increased risk of developing type 1 diabetes /." Connect to full text via ProQuest. IP filtered, 2006.

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Thesis (Ph.D. in Epidemiology) -- University of Colorado, 2006.
Typescript. Includes bibliographical references (leaves 134-160). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

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41

Beildeck, Marcy Ellen. "The role of vitamin D and the vitamin D receptor in TCF-4 regulation and silencing of CYP24A1." Connect to Electronic Thesis (CONTENTdm), 2009. http://worldcat.org/oclc/454140383/viewonline.

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42

Ousley, Amanda. "Engineering the human vitamin D receptor to bind a novel small molecule: investigating the structure-function relationship between human vitamin d receptor and various ligands." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/39580.

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The human vitamin D receptor (hVDR) is a member of the nuclear receptor superfamily, involved in calcium and phosphate homeostasis; hence implicated in a number of diseases, such as Rickets and Osteoporosis. This receptor binds 1α,25-dihydroxyvitamin D3 (also referred to as 1,25(OH)2D3) and other known ligands, such as lithocholic acid. Specific interactions between the receptor and ligand are crucial for the function and activation of this receptor, as implied by the single point mutation, H305Q, causing symptoms of Type II Rickets. In this work, further understanding of the significant and essential interactions between the ligand and the receptor were deciphered, through a combination of rational and random mutagenesis. A hVDR mutant, H305F, was engineered with increased sensitivity towards lithocholic acid, with an EC50 value of 10 µM and 40 + 14 fold activation in mammalian cell assays, while maintaining wild-type activity with 1,25(OH)2D3. Furthermore, via random mutagenesis, a hVDR mutant, H305F/H397Y, was discovered to bind a novel small molecule, cholecalciferol, a precursor in the 1α,25-dihydroxyvitamin D3 biosynthetic pathway, which does not activate wild-type hVDR. This variant, H305F/H397Y, binds and activates in response to cholecalciferol concentrations as low as 100 nM, with an EC50 value of 300 nM and 70 + 11 fold activation in mammalian cell assays.

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43

Ellison, Tara Ingrid. "The vitamin D endocrine system in skin uncoupling the actions of the vitamin D receptor and its ligand keratinocytes /." Cleveland, Ohio : Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1212784762.

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44

Sutton, Amelia L. "The Regulation and Function of 1,25-Dihydroxyvitamin D3-Induced Genes in Osteoblasts." Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1121820822.

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Issa, Chahira Taha Mah D. Ibrahim. "Relação entre perfil cardiometabólico, status de vitamina d e polimorfismo bsmi do gene vdr em idosos." Universidade Federal da Paraíba, 2014. http://tede.biblioteca.ufpb.br:8080/handle/tede/4307.

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The high prevalence of hypovitaminosis D in the elderly population is identified as a potential risk factor for the development of cardiovascular diseases. The vitamin D receptor (VDR) is present in various body cells and polymorphisms of the gene encoding it can affect the cell responses to vitamin D. Therefore, this study aimed to evaluate the relationship between cardiometabolic profile, vitamin D status and BsmI polymorphism of the VDR gene in non-institutionalized elderly subjects. An observational cross-sectional study was conducted with a random and representative sample of 142 elderly subjects selected by conglomerate and recruited from a municipal assistance program. Clinical and nutritional, biochemical and inflammatory profiles, oxidative stress and genotyping for BsmI polymorphism were evaluated. For statistical analysis of data, significance level of p < 0.05 was adopted. Participants had mean age of 69.9 (7.0) years, BMI of 28.3 (4.4) kg / m² and 80.3 % were women. The prevalence of levels of 25 (OH) D < 30 ng / ml was 40.8 % (n = 58), three of them were deficient (25(OH) D < 20 ng / ml) and 55 were insufficient (25(OH) D between 21-29 ng/mL). The influencing factors associated with hypovitaminosis D were gender and fish consumption. The INSUF/DEF group showed fasting blood glucose and MDA values significantly higher when compared to the SUF group. The BsmI polymorphism analysis results showed allelic frequency for the SUF group of B = 0.49 and b = 0.51 and for INSUF/DEF group of B = 0.38 and b = 0.62. The frequency of homozygous bb was significantly associated with lower serum total cholesterol and LDL cholesterol concentrations compared to Bb both in the general population as in the SUF group, whose association was not observed in the INSUF/DEF group. Among individuals with bb, INSUF/DEF group showed higher levels of triglycerides and VLDL cholesterol. It was concluded that blood glucose levels and oxidative stress are increased in elderly subjects with hypovitaminosis D. The presence of genotype bb with adequate vitamin D levels resulted in lower total and LDL cholesterol levels, which benefit is lost when hypovitaminosis D is present. Therefore, low levels of vitamin D can be considered a risk factor for the development of cardiovascular diseases.
A alta prevalência de hipovitaminose D em idosos é identificada como um fator de risco potencial para o desenvolvimento de doenças cardiovasculares. O receptor de vitamina D (VDR) está presente em diversas células do corpo e polimorfismos no gene que o codifica podem influenciar nas respostas celulares à vit. D. Portanto esse estudo teve como objetivo avaliar a relação entre perfil cardiometabólico, status de vitamina D e polimorfismo BSMI do gene VDR em idosos não institucionalizados. Foi realizado um estudo transversal observacional com amostra aleatória e representativa de 142 idosos, selecionada por conglomerado e recrutada em um programa assistencial municipal. Foram avaliados: perfis clínico-nutricional, bioquímico e inflamatório, estresse oxidativo e genotipagem para o polimorfismo BsmI. Para análise estatística dos dados, foi considerado nível de significância p<0,05. Os participantes tinham idade média de 69,9 (7,0) anos, de IMC 28,3(4,4) Kg/m² e 80,3% eram mulheres. A prevalência de níveis de 25(OH)D < 30 ng/mL foi de 40,8% (n= 58), estando três deles deficientes (25(OH)D <20 ng/mL) e 55 com insuficiência (25(OH)D entre 21-29 ng/mL). A média de 25(OH)D foi 36,5(5,8) ng/dL entre os SUF e 25,7 ± 3,3ng/dL nos INSUF/DEF. Indivíduos brancos tiveram percentual significativamente maior de inadequação de níveis de vit. D em relação aos pardos e negros (p = 0,024). Entre o consumo dos principais alimentos fonte de vit. D foi encontrada relação positiva entre consumo de peixe e níveis de vit. D (p = 0,000). O grupo INSUF/DEF apresentou valores de glicemia de jejum significativamente mais elevados (p = 0,022) comparado ao SUF. O estresse oxidativo foi significativamente mais elevado no grupo INSUF/DEF em relação ao grupo SUF (p = 0,003). Os resultados da análise do polimorfismo BsmI do gene do VDR mostraram frequência alélica para o grupo SUF: B= 0,49 e b=0,51 e INSUF/DEF: B=0,38 e b=0,62 com p=0,051. A frequência de homozigoto bb foi significativamente associada com menores concentrações séricas de colesterol total e colesterol LDL, em relação ao BB e Bb, tanto na população em geral como no grupo SUF, associação não observada no grupo INSUF/DEF. Conclui-se que glicemia e estresse oxidativo estão aumentados em idosos com hipovitaminose D. A presença do genótipo bb, em condições adequadas de vit D sérica, resultou em níveis menores de colesterol total e LDL, este benefício se perde quando há insuficiência/deficiência de D. Portanto, baixo nível sérico de 25(OH)D pode ser considerado fator de risco cardiovascular.

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Townsend, Kelly. "Mechanisms of resistance towards the vitamin D receptor in breast cancer." Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423420.

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Although best known for its role in maintenance of calcium homeostasis and bone metabolism, 1,25(OHhD3 also regulates proliferation, differentiation and apoptosis of epithelial cells from a range of tissues, including breast epithelial cells. However, reflecting the growth in this knowledge, over the last twenty years there has been significant interest in the antiproliferative actions of 1,25(OH)2D3 in normal physiology and their potential impact as a novel chemotherapy. The therapeutic impact of 1,25(OHhD3 and its synthetic analogs in cancer has been limited, not only because of the calciotropic side-effects, but also because of the variable sensitivity to the hormone. A number of studies have demonstrated that some breast cancer cell lines exhibit extreme resistance to the antiproliferative action of 1,25(OHhD3. For example, MDA-MB-231 cells require concentrations of greater than 1 ).lM to inhibit cell or colony proliferation by more than 50%. Therefore the aim of this thesis was to identify possible mechanisms for the apparent insensitivity to the antiproliferative actions of 1,25(OH)2D3 in breast cancer. To investigate this the mRNA expression and activity levels of the components of the 1,25(OHhD3 signalling axis (CYP27Bl, VDR and CYP24) were examined in both a panel of breast cancer cell lines and a cohort of 41 matched breast tumour and normal biopsy pairs (Chapter 3). Furthermore, a transcriptomic approach using an Affymetrix human V133 gene expression array (Affymetrix, UK), was utilised to study the gene expression patterns in MCF-7 and MCF-7Res cells, with and without 1,25(OH)2D3 treatment, in order to identify novel genes involved in both 1,25(OHhD3 sensitivity and resistance (Chapter 4). The data demonstrated that all components of the vitamin D signalling axis were expressed at the mRNA level and that both 1a-hydroxylase and 24-hydroxylase enzymes were active in a number of breast cancer cell lines, and in normal breast and the paired breast tumour tissue. Furthermore, all expression levels were elevated in the breast tumours and CYP24 expression was deregulated in breast tumours. Moreover, the increase in CYP27B 1 expression was possible associated with an immune infiltrate of tumour associated macrophages indicated by the fact that with the increased tumour expression of CYP27B 1 mRNA there was a corresponding increase in both TLR-4 and CD14 mRNA expression, which together form part of the macrophage endotoxin response system (Chapter 3). Furthermore, the transcriptomic approach identified a number of possible critical VDR targets involved in 1,25(OH)2D3 resistance including, CD44, ILIl, GADD45a, IGFBP-3, EGFR, ZNF38 and TGF-~2. The role of TGF-~2 was investigated further and a 24 hour time course demonstrated that 1,25(OHhD3 resistant cells did not upregulate TGF-~2 in response to l,25(OHhD3 treatment whereas both the sensitive MCF-7 and non tumourogenic MCF12A cells did. Furthermore treatment with TGF-~2 sensitises resistant cells to the antiproliferative effect of 1,25(OH)2D3 and there was evidence to suggest that TGF-~2 and 1,25(OHhD3 coregulate the expression of VDR target genes as indicated by the increased upregulation of the strongly responding VDR target gene CYP24 following co-treatment (Chapter 4). In conclusion, the data presented in this thesis has identified possible mechanisms of resistance towards the VDR in breast cancer cells, including deregulated autocrine metabolism 1,25(OH)2D3, and the inability of cancer cells to upregulate TGF-~2 following l,25(OHhD3 treatment.

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Carrasco, Tiffani, Kent M. Scruggs, Brooke Beasley, and Michelle Chandley. "Vitamin D receptor gene expression in human and mouse cingulate cortex." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/65.

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Autism Spectrum Disorder (ASD) is characterized by a variety of social, sensory, and developmental symptoms. It is estimated that there are 66 cases per 10,000 children in the United States, placing the U.S. in the top ten countries with the highest prevalence of autism. Japan currently has the highest rate at 161 cases per 10,000. There is currently no known cure for this developmental disorder and the diagnostic protocol is not very clear. Those diagnosed are likely to face years of therapy and exposure to different medications to treat the symptoms. However, one risk factor that has received more attention in recent studies is that of Vitamin D and its relationship with ASD. It has been shown that environmental factors can lead to gene expression changes that may affect social behaviors, a core deficit of ASD. Vitamin D deficiencies during development can lead to the upregulation of DNA-repair genes and maternal deficiencies during pregnancy which may inhibit gene repair in the developing fetus. Deficits in Vitamin D have been linked to an increase in the autoimmune response of the body and are thought to lower the immune system’s attack on infections. Quantitative PCR was used to evaluate vitamin D receptor expression in human and mouse homogenate brain tissue punches from the cingulate cortex to determine Vitamin D receptor expression levels. Associations between Vitamin D and ASD may bring us one step closer to determining whether a simple addition of Vitamin D during the prenatal period could help decrease the risk of a developmental disorder such as autism.

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Egwuekwe, Ejike Roland. "Vitamin D Receptor Gene Polymorphisms Knowledge And Breast Cancer In Texas." ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/6199.

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Breast cancer is a world health problem and is a leading cause of cancer-related death among women in the United States. However, breast cancer risks were reported to be reduced through exposure to Vitamin D through its Receptors identified as the p53 target gene. The purpose of this study was to assess the associations between VDR gene polymorphisms knowledge/awareness and decisions to reduce breast cancer risks and likelihood of mammogram screening among women in Texas. Data from survey were used. Roy adaptation model was the theoretical framework that guided this quasi- experimental, quantitative research. The dependent variables were decisions to reduce breast cancer risks and likelihood of mammogram screening. The independent variables were knowledge about VDR gene polymorphisms and exposure to vitamin D. The covariates were level of education, awareness, lifestyle, breast self-exams, mammograms, age, early menarche, late menopause, and family history of breast cancer. The chi-square test and regression analysis were used to test the stated research hypotheses and to answer the research questions. Knowledge of VDR gene polymorphisms and exposure to vitamin D were not significantly associated with breast cancer risk, ï?£2 (3, N= 250) =3.84, p > 0.05. Also, awareness of the risk factors for breast cancer was not significantly associated with decisions to go for mammogram screenings or to enroll in breast cancer risk-reduction programs, ï?£2 (3, N= 250) =1.58, p > 0.05. To advocate for the promotion of awareness of the importance of pharmacogenetic testing for VDR gene polymorphisms for early detection of breast cancer, which would help to undertake appropriate therapeutic measures in a timely manner to prevent cancer metastasis, further research is warranted.

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Goncalves, Renata. "Interactions entre la signalisation estrogénique et la vitamine D dans les cellules testiculaires." Thesis, Normandie, 2018. http://www.theses.fr/2018NORMC411/document.

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La 1α,25(OH)2 vitamine D3 (1,25-D3) est synthétisée à partir du cholestérol par l'exposition solaire de la peau. Les effets de cette hormone sont médiées par le récepteur de la vitamine D (VDR) dans le noyau et à la membrane plasmique, et avec le récepteur PDIA3 ils médient des effets génomiques et non-génomique. La vitamine D joue un rôle important dans la reproduction, puisque la réduction de la fertilité a été observée chez les rats déficients en vitamine D. L'estradiol (E2) est synthétisé à partir de la testostérone par l'enzyme aromatase (CYP19). L’E2 a des effets génomiques et non génomiques médiée par les récepteurs ESR1, ESR2 et GPER. L’objectif de ce travail a été d’étudier l’effet de l’E2 sur le métabolisme et les voies de signalisation de la vitamine D dans des testicules des rats à différents âges ainsi qu’une perturbation éventuelle initiée par un perturbateur endocrinien à activité estrogénique, le Bisphénol A (BPA). Dans le première axe de travail, trois protocoles expérimental (PE) ont été réalisés, où l’E2 et le BPA ont été administrés: traitement de J15pp à J30pp et euthanasie immédiate à J30 (PE1), traitement de J15 à J30 et euthanasie différée à J75 (PE2) et traitement à l’âge adulte de J60 à J75 et euthanasie immédiate à J75 (PE3). Dans le PE1, le traitement avec l’E2 a diminué l'expression du CYP27A1. L’E2 et le BPA ont diminué l'expression du VDR. Cet effet n'a pas été vérifié dans l'expression de la protéine VDR. Dans le PE2, l’E2 a augmenté l'expression des gènes VDR, PDIA3 et CYP27A1, et l'expression de la protéine VDR et CYP27A1. Les traitements n’ont eu aucun effet dans le PE3, ce qui indique qu’un traitement en période prépubère entraîne à la fois un effet immédiat et différé alors que le traitement à l’âge adulte semble sans effet. Dans le deuxième axe de travail, des effets non-génomiques du BPA ont été étudiés par la technique d’afflux de 45Ca2+ dans les testicules de rat prépubères. Le BPA a stimulé l’afflux de 45Ca2+ de manière un peu pareille avec les effets de l’E2. Cet effet semble ne pas impliquer les récepteurs classiques des estrogènes, mais semble se produire de manière compatible avec l'activation d'un récepteur couplé à la protéine G, comme le GPER. Cet effet se produit par la modulation de la fonction des canaux ioniques, comme des canaux potassiques, TRPV1 et des canaux chlorés. Aussi le BPA module le calcium du stock intracellulaire par l’inhibition de la SERCA et l’activation du récepteur IP3. Également des protéines kinases PKA, PKC, MEK et p38MAPK participent de l’effet du BPA, qui pourrait déclencher un cross talk avec les voies de signalisation nucléaires résultant la médiation des réponses génomiques. Dans le troisième axe de travail, l'expression de certains gènes impliqués dans le métabolisme et la signalisation de 1,25-D3 et E2 a été analysée dans des cellules de Leydig. La 1,25-D3 a diminué l'expression du CYP27A1, un effet qui a également été observé lorsque les cellules étaient co-incubées avec l'E2. L’E2 a diminué l'expression des gènes ESR1 et CYP19. Les deux hormones ont démontré un mécanisme de retours négatifs sur leur métabolisme dans ces cellules. Des effets non génomiques ont été étudiés dans ces cellules, où l’E2 semble avoir un effet inhibiteur tandis que la 1,25-D3 a stimulé l'afflux de 45CA2+. A partir de ces résultats, nous pouvons affirmer que la 1,25-D3, l’E2 et le BPA ont des effets moléculaires importants dans le système reproducteur masculin, par l'expression génique des récepteurs et des enzymes impliqués dans le métabolisme des hormones 1,25-D3 et E2. De plus, les résultats obtenus renforcent la théorie selon laquelle il existe une relation entre les voies de signalisation de la 1,25-D3 et l’E2. Comme la 1,25-D3 et l'E2, le BPA stimule également les effets non-génomiques impliqués dans la signalisation du calcium
1α,25-dihydroxyvitamin D3 (1,25-D3), the active form of vitamin D, is synthetized from cholesterol by skin exposure to the sun. This hormone’s actions are mediated by vitamin D receptor (VDR) in the nucleus and in the plasma membrane, resulting in genome actions like gene expression regulation. VDR can also be found in the plasmatic membrane, and together with PDIA3 receptor they mediate 1,25-D3 non-genomic actions. Vitamin D has an important role in reproductive function, since fertility reduction was observed in vitamin D deficient rats, as well as VDR and 1α-hydroxylase deficiency. In these animals, calcium and estrogen supplementation was able to reverse the deleterious effects in reproductive function, indicating that there is a relation between 1,25-D3 and estrogens signalling pathways. Estradiol (E2) is synthetized from testosterone by aromatase enzyme (CYP19). E2 is found in high levels in the male reproductive function, and like 1,25-D3 can induce genomic and non- genomic actions, mediated by ESR1, ESR2 and GPER receptors. Bisphenol A (BPA) is a xenoestrogen utilized in plastic industry, capable of modulating the endocrine system through E2 receptors. The aim of this work was to study metabolism and signaling pathways interactions between 1,25-D3 and E2, as well as BPA influence in testicular cells. In the first line of work, three treatment protocols (TP) were realized, where E2 and BPA were administrated in rats between 15th and 30th days, were a portion of the animals were euthanized at the last day of treatment (TP1) and another portion was kept alive after the treatment until euthanized at adult age with 75 days (TP2). A third animal group also received the same treatments when adults (TP3). In TP1, E2 treatment decreased CYP27A1 gene expression. E2 and BPA decreased VDR gene expression. This effect was not verified in VDR protein expression. In TP2, E2 increased VDR, PDIA3 and CYP27A1 gene expression, and VDR and CYP27A1 protein expression, indicating a compensatory effect over gene expression inhibition in prepubertal age. In TP3, treatments did not change gene expression, indicating that prepubertal age is more susceptible to estrogen exposure. In the second line of work, non-genomic effects of BPA were studied through 45Ca2+ influx in prepubertal rat testis. BPA stimulated 45Ca2+ influx in a similar manner to E2. This effect was independent of classical ERs, consistent with a G protein-coupled receptor mechanism, probably GPER. This effect involves the modulation of ionic channels, such as K+, TRPV1 and Cl- channels. Furthermore, BPA is able to modulate calcium from intracellular storages by inhibiting SERCA and activating IP3 receptor/Ca2+ channels at the endoplasmic reticulum and activate kinase proteins, such as PKA and PKC. The rapid responses of BPA on calcium influx could, in turn, trigger a cross talk by MEK and p38MAPK activation and also mediate genomic responses. In the third line of work, the expression of some genes involved in 1,25-D3 and E2 metabolism and signalling were analysed in Leydig cells. 1,25-D3 decreased CYP27A1 gene expression, an effect that was also observed when cells were coincubated with 1,25-D3 and E2. E2 decreased ESR1 and CYP19 gene expression. Both hormones demonstrated an negative feedback mechanism over their on metabolism in these cells. Non-genomic effects were also studied in these cells, where E2 seems to have an inhibitory effect while 1,25-D3 was able to stimulate calcium influx. From these results we can conclude that 1,25-D3, E2 and BPA have important molecular effects in the male reproductive system, through gene expression control over receptors and enzymes involved in the metabolism of the steroid hormones studied. These results also reinforce the theory that there is a relationship between 1,25-D3 and E2 signalling pathways, as well as 1,25-D3, E2 and BPA also have non-genomic actions in calcium signalling

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Maguire, Orla. "Novel chemo-protective roles of the Vitamin D Receptor in prostate cells." Thesis, University of Ulster, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529507.

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