Dissertations / Theses: 'IGF1'

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Dias, Elaine Oliveira. "Expressão do fator de crescimento similar à insulina 1 e 2 (IGF1 e IGF2) e receptor de IGF1 (IGF1R) no carcinoma papilífero da tireoide." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-24022015-110719/.

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INTRODUÇÃO: Acredita-se que os fatores de crescimento insulina símile 1 (IGF1) e IGF2 tenham um papel chave na progressão de tumores, resistência à apoptose e terapias. A resistência à insulina tem sido associada ao aumento do volume tireoidiano e aumento do risco de desenvolver nódulos e câncer de tireoide; no entanto, há poucos estudos que avaliaram o papel dos IGFs e seus receptores no carcinoma papilífero de tireoide (CPT) e, até o momento, nenhum estudo foi conclusivo sobre a relação entre a via insulina/IGF e o comportamento do CPT. OBJETIVOS: 1) Estudar a expressão do IGF1, IGF2 e o IGF1R no CPT, incluindo o microcarcinoma papilífero; 2) Correlacionar essa expressão com as características clínicas, variante histopatológica, estadiamento e estratificação de risco. MÉTODOS: Foram selecionados, retrospectivamente, 110 pacientes operados por CPT e atendidos no Ambulatório do Serviço de Endocrinologia do Hospital das Clínicas da FMUSP e separados em dois grupos: 62 microcarcinomas papilíferos (MCP) e 48 CPT > 1,0 cm. A presença e expressão do IGF1, IGF2 e IGF1R foi avaliada, através de exame imunohistoquímico, em 110 tecidos tumorais e 98 tecidos não tumorais (controle). Os casos positivos foram classificados, de acordo com a quantidade de células coradas, em: + (menos de 10% das células); ++ (em 10-50% das células) e +++ (mais de 50% das células). O grau da expressão foi classificada em leve, moderada e forte. A presença e intensidade desses marcadores foram correlacionados com as características clínicas, variante histopatológico, TNM e estratificação de risco. RESULTADOS: O IGF1 e o IGF1R estiveram presentes em 100% e 99% dos CPTs e mostraram-se significativamente hiperexpressos, tanto nos MCPs quanto nos CPTs > 1,0 cm, quando comparados ao tecido adjacente não tumoral (p < 0,001). O IGF2 esteve expresso em 46,7% dos CPTs e mostrou fraca expressão em apenas um tecido não tumoral (p < 0,001). O IGF1 apresentou expressão significativamente maior nos microcarcinomas nos estágios III e IVA quando comparados aos estágios I e II (p=0,022). Não houve diferença significativa na quantidade e intensidade de expressão do IGF1 e IGF1R nos MCT quando comparados aos CPTs > 1,0 cm. O IGF2 apresentou expressão significativamente maior nos MCTs e, nesse grupo, apresentou maior expressão nos tumores multicêntricos (p=0,017) e nos estágios III e IVA, quando comparados aos estagios I e II (p=0,041). CONCLUSÕES: No presente estudo, observamos que o IGF1 e IGF2 foram significativamente mais expressos nos microcarcinomas em estágios mais avançados. O IGF2 apresentou maior expressão nos microcarcinomas papilíferos e esta expressão foi significativamente maior nos tumores multicêntricos
INTRODUCTION: Insulin-like growth factor-1 and 2 (IGF-1 and IGF-2) are believed to play a key role in the progression of tumors, resistance to apoptosis and therapies. The insulin resistence has been associated with increased thyroid volume and increased risk in developing thyroid nodules and thyroid cancer. However, few studies have evaluated the role of IGFs and their receptors on papillary thyroid carcinomas (PTC), and there is no conclusive studies about the relationship between IGF axis and PTC behavior. OBJECTIVES: The aim of this study was to investigate the expression of IGF-1, IGF-2, and IGF-1R in PTC, including papillary microcarcinoma (PTMC), and correlate the expression data with clinical, histologic variants, TNM staging, and risk of recurrence. METHODS: We retrospectively selected 110 paraffin-embedded tumoral tissues from patients with PTC who underwent thyroidectomy at Hospital das Clínicas of FMUSP. These patients were divided into two groups: 62 microcarcinomas (PTMC) and 48 PTC > 1.0 cm. The presence and intensity of expression of IGF-1, IGF-2, and IGF-1R were evaluated through immunohistochemical staining in 110 tumoral tissues, and in 98 non-tumoral tissues (control group). Positive cases were classified according to the numbers of staining cells in: + less than 10% of staining cells; ++ in 10-50% of the staining cells, and +++ in more than 50% of staining cells. The degree of expression was classified as mild, moderate and strong. The presence and degree of IGF1, IGF2, and IGF1R staining were correlated with clinical features, histologic type, TNM staging, and risk stratification. RESULTS: IGF-1 and IGF-1R were expressed in 100% and 99% of PTC, and were significantly overexpressed in both PTMC and PTC > 1.0 cm, in comparison with non-tumoral tissues (control group) (p < 0.001). IGF-2 was expressed in 46.7% of PTC and had mild positivity expression in only one non-tumoral tissue (p < 0.001). IGF1 was significantly overexpressed in PTMC on stage III and IVa and was less expressed in stage I and II. There was no significant difference on IGF1 and IGF1R expression between PTMC and PTC >1.0 cm. IGF-2 presented greater expression in multicentric PTMC (p=0.017), specially in stage III and IVa. CONCLUSIONS: In our study, both IGF-1 and IGF2 were significantly overexpressed in PTMC group in advanced stages. IGF-2 was also significantly overexpressed in PTMC multicentric tumors

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Jakoby, Judith Martina [Verfasser], and Regine [Akademischer Betreuer] Süss. "Aktives liposomales Targeting IGF1-Rezeptor-exprimierender Tumoren." Freiburg : Universität, 2014. http://d-nb.info/1123481849/34.

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Wallborn, Tillmann. "Klinisches Erscheinungsbild und zugrundeliegende molekularbiologische Mechanismen der heterozygoten V599E-IGF-I Rezeptormutation." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-90100.

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Untersuchungen haben gezeigt, dass unterdurchschnittlich leichte Neugeborene für zahlreiche Erkrankungen ein erhöhtes Risiko tragen. Beschrieben ist unter anderem das vermehrte Auftreten psychosozialer Probleme sowie metabolischer und kardiovaskulärer Spätfolgen. Inzwischen sind zahlreiche mögliche Ursachen einer intrauterinen und postnatalen Wachstumsretardierung beschrieben worden. Unter diesen Ursachen finden sich auch genetische Veränderungen von Proteinen der endokrinologischen Wachstumsregulierung. So wurden Mutationen im GH1 Gen, in Entwicklungsgenen von GH produzierenden Zellen, im IGF-I Gen und schließlich auch im IGF-I Rezeptor Gen identifiziert. Mutationen im letztgenannten Gen stellen den neuesten Forschungszweig dar und wurden bisher weltweit bei lediglich 19 Patienten festgestellt. Mit dieser Arbeit wird ein weiterer Patient mit einer heterozygoten IGF-I Rezeptormutation beschrieben. Neben einer ausführlichen klinischen Beschreibung war die Analyse der Kausalzusammenhänge von Mutation und klinischem Bild Hauptziel dieser Studie. Über eine ausgeprägte intrauterine und postnatale Wachstumsretardierung hinaus präsentierte die betroffene Patientin eine mentale Entwicklungsverzögerung. Durch verschiedene molekularbiologische Methoden konnte eine gestörte intrazelluläre Prozessierung des veränderten Rezeptorproteins nachgewiesen werden. Beobachtet wurde eine fehlende Zelloberflächenexpression aufgrund einer Retention von Rezeptorvorstufen im Endoplasmatischen Retikulum. Damit wurde ein neuer Mechanismus der IGF-I Resistenz beschrieben.

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Harmel, Eva-Maria Sophia. "Klinisches Erscheinungsbild und funktionelle Charakterisierung eines Patienten mit einer heterozygoten Exon 6 Deletion im IGF1R." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-163923.

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Hintergrund: Der Insulin-like growth factor receptor (IGF1R) spielt eine zentrale Rolle bei Wachstumsprozessen. Heterozygote IGF1R-Mutationen führen durch eine partielle IGF1-Resistenz zu Kleinwuchs. Methoden: Auxologische und endokrinologische Daten des Patienten wurden erhoben. Anhand von Fibroblasten wurde die IGF1R-Deletion charakterisiert und die Auswirkungen auf die mRNA- und Protein-Expression sowie die Signaltransduktion untersucht. Ergebnisse: Der Junge, der eine heterozygote Exon 6 Deletion im IGF1R – durch Alu-Rekombination verursacht – und eine heterozygote SHOX-Variante (p.Met240Ile) in seinem Genom vereint, kam ‚appropriate for gestational age‘ zur Welt, entwickelte aber postnatal eine Wachstumsretardierung. Die Endokrinologischen Daten waren unauffällig. Der Patient zeigt keine Stigmata, die bei anderen IGF1- oder SHOX-Mutationsträgern beschrieben wurden. Durch Nonsense-Mediated mRNA Decay kommt es zu einer Dosisreduktion der IGF1-Rezeptoren und einer entsprechenden verminderten Aktivierung der Rezeptoren, nicht aber des Signalwegs. Zusammenfassung: Der Patient trägt eine bisher unbeschrieben heterozygote IGF1R-Deletion, die zu Kleinwuchs führt. Ursächlich dafür ist eine durch die Mutation verursachte Dosisreduktion der IGF1-Rezeptoren.

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Müller, Eva. "Klinische und funktionelle Charakterisierung einer stark wachstumsretardierten Patientin mit einer zusammengesetzten heterozygoten Pericentrinmutation und einer heterozygoten IGF1-Rezeptor Mutation." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-131321.

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Die menschliche Entwicklung ist charakterisiert durch ein rasches fetales Wachstum, ein langsames postnatales Wachstum, ein kontinuierliches Wachstum im Laufe der Kindheit sowie einen Wachstumsschub während der Pubertät. In den letzten Jahren wurde gezeigt, dass Mutationen in den Genen des Pericentrins (PCNT) und des Insulin-like growth factor-1 Rezeptors (Insulin ähnlicher Wachstumsfaktor Typ 1 Rezeptor, IGF1R) seltene Auslöser von prä- und postnataler Wachstumsrestriktion darstellen können. In dieser Arbeit wird eine stark wachstumsretardierte Patientin mit zusammengesetzter heterozygoter PCNT-Mutation und heterozygoter IGF1R-Mutation beschrieben. Ziel dieser Arbeit war zum einen die ausführliche klinische Charakterisierung der Patientin. Zum anderen sollte auf zellulärer Ebene überprüft werden, inwieweit die genannten Mutationen den Phänotyp der Patientin erklären. Um die funktionellen Zusammenhänge zu untersuchen, wurden in vitro Assays durchgeführt. Hierfür standen neben mit dem mutierten Rezeptor transfizierte IGF1R-defiziente Mausfibroblasten (R--Zellen) auch humane Fibroblasten zur Verfügung. Es wurden die totale und die extrazelluläre Rezeptorexpression, die IGF1 induzierte Stimulierung und die Signaltransduktion des mutierten IGF1R untersucht. Weiterhin wurde die proliferative Kapazität der Patientenfibroblasten analysiert. Die Ergebnisse dieser Analysen ergaben keine relevanten Funktionseinschränkungen des mutierten IGF1R. Demgegenüber steht eine reduzierte Zellproliferation der Patientenfibroblasten. Die zugrunde liegenden Mechanismen der verminderten Proliferationskapazität sind womöglich den PCNT-Mutationen zuzurechnen. In Versuchen zur IGF1 induzierten Proliferationssteigerung konnte die Proliferation der Patientenfibroblasten zwar kurzfristig stimuliert werden, bei längerer IGF1-Stimulation konnte jedoch das bestehende Proliferationsdefizit nicht ausgeglichen werden. Die genauen molekularbiologischen Auswirkungen der PCNT-Mutation in Bezug auf den ausgeprägten Phänotyp der Patientin müssen in zukünftigen Arbeiten noch weiter aufgeklärt werden.

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Besen, Lisia Schaefer. "Concentração de IGF1 livre e insulina no fluido folicular e a expressão folicular dos receptores de IGF1 durante a foliculogênese da égua." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/150241.

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O objetivo deste estudo foi analisar as concentrações do fator de crescimento semelhante à insulina tipo 1 (IGF1) e insulina (INS) no fluido folicular durante foliculogênese em éguas, e localizar o receptor tipo 1 de IGF (IGF1R) nas paredes foliculares. Durante a estação reprodutiva, 40 éguas mestiças enviadas para abate em matadouro, com idades variando entre 6 e 16 anos foram utilizadas. As éguas foram abatidas de forma humanitária. Os tratos reprodutivos internos foram recuperados dentro de 10 min após o abate, ovários de éguas cíclicas foram separados do resto do aparelho. As éguas foram classificadas em quatro grupos: G1 – Folículo ≤ 13,5 mm e CL identificável; G2 – Folículo de 13,6 - 22,5 mm e CL identificável; G3 – Folículo de 22,6 - 31,5 mm e CL identificável; G4 – Folículo ≥ 31,6 mm e CL difícil de identificar. O fluido folicular (FF) foi aspirado e armazenado a -80 ° C até a sua utilização. Após a punção do FF, um fragmento da porção ventral da parede folicular foi removido para realizar a imunohistoquímica para localização de receptores IGF1R. O IGF1 livre foi determinado por ensaio imunoradiométrico. A INS foi determinada por um radioimunoensaio de fase líquida. A concentração de IGF1 livre e INS no FF aumentou com o crescimento folicular (P < 0,05). O escore imunohistoquímico de IGF1R nas células da granulosa e da teca interna da parede folicular equina em diferentes grupos aumentou (P < 0,05) com aumento folicular. Concluímos que as concentrações de IGF1 livre e INS no FF e de IGF1R em paredes foliculares de éguas aumentam com o crescimento folicular durante a foliculogênese, dando evidência do papel importante do IGF1 e INS no desenvolvimento folicular, e uma interação entre ambos hormônios na fisiologia reprodutiva ovariana. Sendo a égua um modelo de pesquisa para estudos comparativos na dinâmica folicular para consideração em mulheres, a conclusão deste estudo pode ser aplicada, também, a humanos.
The aim of this study was to analyze free type 1 insulin-like growth factor (IGF1) and insulin (INS) concentrations in follicular fluid during folliculogenesis in mares, and to localize type 1 IGF receptor (IGF1R) on follicular walls. During the breeding season, 40 mixed-breed mares sent to slaughter at an abattoir, with ages ranging between 6 to 16 years were used. Mares were humanely slaughtered. Internal reproductive tracts were recovered within 10 min after slaughter; ovaries of cyclic mares were separated from the rest of the tract. Mares were categorized into four groups: G1 – Follicle ≤ 13.5 mm and CL identifiable; G2 – Follicle of 13.6 to 22.5 mm and CL identifiable; G3 – Follicle of 22.6 to 31.5 mm and CL identifiable; G4 – Follicle ≥ 31.6 mm and CL difficult to identify. The follicular fluid (FF) was aspirated and stored at -80°C until use. After puncture of the FF, a fragment of the ventral portion of the follicular wall was removed to perform immunohistochemistry to localize IGF1R receptors. Free IGF1 was determined by immunoradiometric assay. INS was determined by a liquid phase radioimmunoassay. The concentration of free IGF1 and INS in FF increased with follicle growth (P < 0.05). Immunohistochemical score of IGF1R on granulosa and internal theca cells from equine follicular wall on different groups increase (P < 0.05) with follicular raise. We conclude that free IGF1 and INS concentrations in FF and IGF1R in follicular walls of mares increase with follicular growth during folliculogenesis, giving evidence of important role of IGF1 and INS in follicular development, and an interaction between both hormones in ovarian reproductive physiology. As the mare is a model research for comparative studies in follicular dynamics for consideration in women, the conclusion of this study can be applied to humans also.

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Schneider, Harald Jörn, Nele Friedrich, Jens Klotsche, Sabine Schipf, Matthias Nauck, Henry Völzke, Caroline Sievers, et al. "Prediction of incident diabetes mellitus by baseline IGF1 levels." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-100978.

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Objective: IGF1 is associated with metabolic parameters and involved in glucose metabolism. Low-IGF1 has been implicated in the etiology of glucose intolerance and subjects with pathological causes of either low- or high-IGF1 are at risk of diabetes. We hypothesized that both low- and high-IGF1 levels increase the risk of diabetes and aimed to assess the role of IGF1 in the risk of developing diabetes in a large prospective study. Design: An analysis of two prospective cohort studies, the DETECT study and SHIP. Methods: We measured IGF1 levels in 7777 nondiabetic subjects and assessed incident diabetes mellitus during follow-up. Results: There were 464 cases of incident diabetes during 32 229 person-years (time of follow-up in the DETECT study and SHIP: 4.5 and 5 years respectively). There was no heterogeneity between both studies (P>0.4). The hazard ratios (HRs) of incident diabetes in subjects with IGF1 levels below the 10th or above the 90th age- and sex-specific percentile, compared to subjects with intermediate IGF1 levels, were 1.44 (95% confidence interval (CI) 1.07–1.94) and 1.55 (95% CI 1.06–2.06) respectively, after multiple adjustment. After further adjustment for metabolic parameters, the HR for low-IGF1 became insignificant. Analysis of IGF1 quintiles revealed a U-shaped association of IGF1 with risk of diabetes. Results remained similar after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline. Conclusions: Subjects with low- or high-IGF1 level are at increased risk of developing diabetes.

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Parente, Pereira A. C. "Study of two bipolar susceptibility genes : Slynar and IGF1." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18571/.

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Linkage studies have implicated the 12q22-24 region in susceptibility to bipolar disorder. In this region alleles at the “Slynar” and Insulin Like Growth Factor 1 (IGF1) genes showed association with bipolar disorder. The Slynar gene is contained within a region of 278 kb on chromosome 12q24 and expresses the sequence AY070435 in the human brain. AY070435 has no known function. A Macaque brain expressed cDNA which is highly homologous to human AY070435 has been cloned and sequenced. To further characterise the human Slynar gene and expressed mRNA transcript studies were carried out to identify Slynar in the mouse and in human neuroblastoma cell lines. Exhaustive efforts were taken to find a mouse homologue but these proved negative. Slynar shared no homology, or partial homology with any other gene in the human genome. The other 12q24 bipolar susceptibility gene IGF1 is highly expressed in the human brain and a well known for its neuromodulatory functions. IGF1 protein has been shown to have an antidepressant and anxiolytic-like effect in the mouse brain. On a genome wide association study (GWAS) with the UCL case control sample, IGF1 was found to be associated to disease with 5 SNPs showing association within the gene. In order to further implicate IGF1 and find the aetiological base pair changes responsible for disease, IGF1 was sequenced. New three new non database SNPs, three previously characterised polymorphisms and a CA repeat were found and genotyped in an extended UCL sample of 1,000 cases and 1,000 controls. One of the novel SNPs and the CA repeat, both located in the promoter region, were associated with bipolar disorder. Haplotype analysis of the GWAS and new markers data confirmed association to bipolar disorder.

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Schneider, Harald Jörn, Nele Friedrich, Jens Klotsche, Sabine Schipf, Matthias Nauck, Henry Völzke, Caroline Sievers, et al. "Prediction of incident diabetes mellitus by baseline IGF1 levels." BioScientifica, 2011. https://tud.qucosa.de/id/qucosa%3A26329.

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Objective: IGF1 is associated with metabolic parameters and involved in glucose metabolism. Low-IGF1 has been implicated in the etiology of glucose intolerance and subjects with pathological causes of either low- or high-IGF1 are at risk of diabetes. We hypothesized that both low- and high-IGF1 levels increase the risk of diabetes and aimed to assess the role of IGF1 in the risk of developing diabetes in a large prospective study. Design: An analysis of two prospective cohort studies, the DETECT study and SHIP. Methods: We measured IGF1 levels in 7777 nondiabetic subjects and assessed incident diabetes mellitus during follow-up. Results: There were 464 cases of incident diabetes during 32 229 person-years (time of follow-up in the DETECT study and SHIP: 4.5 and 5 years respectively). There was no heterogeneity between both studies (P>0.4). The hazard ratios (HRs) of incident diabetes in subjects with IGF1 levels below the 10th or above the 90th age- and sex-specific percentile, compared to subjects with intermediate IGF1 levels, were 1.44 (95% confidence interval (CI) 1.07–1.94) and 1.55 (95% CI 1.06–2.06) respectively, after multiple adjustment. After further adjustment for metabolic parameters, the HR for low-IGF1 became insignificant. Analysis of IGF1 quintiles revealed a U-shaped association of IGF1 with risk of diabetes. Results remained similar after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline. Conclusions: Subjects with low- or high-IGF1 level are at increased risk of developing diabetes.

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Silva, Liliana de Jesus Vieira da. "Central effects of insulin and IGF1 in diabetic neuropathy." Master's thesis, Universidade de Aveiro, 2010. http://hdl.handle.net/10773/8778.

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Mestrado em Biologia Molecular e Celular
Este estudo avaliou se o tratamento de ratos diabéticos induzidos com estreptozotocina, com insulina ou factor de crescimento derivado da insulina (IGF1), em doses que não revertem a hiperglicemia, afectam os sinais comportamentais da neuropatia diabética e a ativação neuronal na medula espinhal. Foi também avaliada a participação de algumas das principais áreas do tronco cerebral (VLPAG), envolvidas na modulação descendente da dor. Uma semana após a indução da diabetes, foi iniciado o tratamento dos animais, 3 vezes por semana durante 3 semanas, com soro fisiológico, insulina (2 IU) ou IGF1 (2,5 mg / Kg). O tratamento com insulina ou IGF1 preveniu sinais comportamentais de neuropatia diabética, denominada alodínia mecânica. A avaliação comportamental dos animais através do teste de formol evidenciou que, quer a insulina quer o IGF1, previnem a elevada frequência de espasmos observados nos ratos diabéticos, para valores semelhantes aos dos controlos. Quanto à activação nociceptiva da expressão de c-fos no corno dorsal da medula espinal, esta foi inibida por ambos os tratamentos. A melhoria das acções comportamentais e da activação nociceptiva dos neurónios espinhais mediada pelo tratamento com IGF1 é susceptível de ser devida aos efeitos na modulação dolorosa descendente proveniente do tronco cerebral, mediada pela serotonina e noradrenalina. Ratos diabéticos apresentaram elevados números de neurónios imunorreactivos para TpH (marcador de neurónios serotoninérgicos) no RVM, ou para TH (marcador de neurónios noradrenérgicos) no núcleo celular noradrenérgico A5 (pontine). Estes números foram normalizados para níveis controlo, mas apenas quando tratados com IGF1, uma vez que a insulina não afecta estes parâmetros. Observou-se que os níveis de serotonina e noradrenalina na medula espinhal estavam aumentados, bem como os ratos tratados com insulina. Estes resultados evidenciaram que a insulina e o IGF1 possuem diferentes efeitos no sistema nervoso, sendo que os efeitos centrais devem-se essencialmente ao IGF1.
This study evaluates if the treatment of Streptozotocin-induced diabetic rats with insulin or insulin growth factor 1 (IGF1), in doses that do not reverse hyperglicemia, affect behavioural signs of diabetic neuropathy and neuronal activation at the spinal cord. The participation of main brainstem areas involved in descending modulation of pain was also evaluated (VLPAG). One week after diabetes induction, the animals were injected, 3 times per week, with saline, insulin (2 IU) or IGF1 (2.5 mg/Kg) during 3 weeks. Treatment with insulin or IGF1 prevented behavioural signs of diabetic neuropathy, namely mechanical allodynia. Behavioural evaluation of the animals by the formalin test showed that insulin and IGF1 strongly prevented the higher frequency of flinching behavior to values similar to controls. Nociceptive activation of c-fos expression induced by formalin at the spinal dorsal horn was inhibited by both treatments. The improvement of behavioural actions and nociceptive activation of spinal neurons mediated by IGF1 treatment are likely to be due to effects in descending pain modulation from the brainstem, mediated by serotonin and noradrenaline. Diabetic rats presented higher numbers of neurons immunoreactive for TpH (marker of serotoninergic neurons) at the rostroventromedial medulla or for TH (marker of noradrenergic neurons) at the pontine A5 noradrenergic cell group. These numbers were normalized to control levels only after IGF1 treatment, but not after insulin. The levels of serotonin and noradrenaline at the spinal cord were increased in non treateddiabetic rats and insulin treated-rats. These results show that insulin and IGF1 appear to have different effects on the nervous system, with more central effects being ascribed to IGF1.

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Linay, Fabien. "Rôle du récepteur IGF1 R dans l'homéostasie de la peau murine." Paris 6, 2012. http://www.theses.fr/2012PA066239.

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Souza, Karla Simone Costa de. "Estudo da influ?ncia dos genes LRP5, TGFB1, IGF1 e IGF1R no metabolismo ?sseo de pacientes com diabetes mellitus tipo 1." Universidade Federal do Rio Grande do Norte, 2013. http://repositorio.ufrn.br/handle/123456789/19846.

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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico - CNPq
Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES
A osteopatia ? uma complica??o cr?nica do diabetes tipo 1 (DM1). Alguns mecanismosv?m sendo propostos como principais fatores que desencadeiam altera??es no tecido ?sseo, dentreeles: a idade ao diagn?stico, tempo de doen?a, a presen?a de nefropatia e o controle glic?micoinsatisfat?rio. Neste sentido, o objetivo do presente estudo foi avaliar a express?o de RNAm dosgenes TGFB1, IGF1 e IGF1R e polimorfismos nos genes LRP5, TGFB1 e IGF1 de pacientes comDM1, e associ?-los com a presen?a de altera??es no metabolismo ?sseo. Foram estudados 100indiv?duos normoglic?micos (NG) e 101 pacientes com DM1, entre 6 e 20 anos. Os pacientesdiab?ticos foram analisados em sua totalidade (grupo DM1), e subdivididos em dois grupos, deacordo com o controle glic?mico: diab?ticos compensados (grupo DM1C) e diab?ticos n?ocompensados (grupo DM1NC). Avaliou-se o controle glic?mico (glicemia de jejum ehemoglobina glicada); a fun??o renal (ureia e creatinina s?ricas, e rela??o albumina/creatinina -RAC urin?ria); e o metabolismo ?sseo (c?lcio total e ionizado, f?sforo, atividade da fosfatasealcalina total - FAL e densidade mineral ?ssea - DMO) dos indiv?duos estudados. Tamb?m foideterminada a express?o do RNAm dos genes TGFB1, IGF1 e IGF1R e polimorfismos nos genesLRP5, TGFB1 e IGF1. A maioria dos indiv?duos com DM1 (65,3%) apresentou controleglic?mico insatisfat?rio (hemoglobina glicada >8%). Em rela??o ? fun??o renal, observou-se umaumento significativo nas concentra??es de ureia s?rica nos grupos DM1, DM1C e DM1NC e umaumento da RAC no grupo DM1NC em rela??o ao NG. No tocante aos marcadores bioqu?micosdo metabolismo ?sseo houve uma diminui??o das concentra??es s?ricas de c?lcio total nos gruposDM1, DM1C e DM1NC, e das concentra??es de c?lcio ionizado no grupo DM1 quandocomparados ao grupo NG. Tamb?m, houve um aumento significativo da atividade da FAL nogrupo DM1 em rela??o ao NG. A DMO estava significativamente diminu?da no grupo DM1quando comparado ao NG, sendo observada uma preval?ncia de 16,7% de indiv?duos diab?ticostipo 1 com baixa DMO. Na an?lise molecular, foram observadas diminui??es significativas naexpress?o dos genes TGFB1 e IGF1, e aumento significativo da express?o do gene IGF1R para ogrupo DM1 quando comparados ao NG. As frequ?ncias genot?picas e al?licas dos polimorfismosestudados foram significativas apenas para o polimorfismo do gene LRP5, demonstrando umaassocia??o deste polimorfismo com a susceptibilidade ao DM1. Por?m, n?o foram observadasassocia??es entre os polimorfismos e a osteopatia diab?tica. Estes resultados sugerem que ocontrole glic?mico insatisfat?rio, em conjunto com a presen?a de fatores de risco e altera??es emgenes envolvidos intimamente no metabolismo ?sseo, interfere na forma??o deste tecido,contribuindo para uma redu??o da DMO.

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Beasley, Brooke, Aubrey Sciara, Tiffani Carrasco, Gregory Dr Ordway, and Michelle Dr Chandley. "Laser Capture Microdissection Analysis of Inflammatory-Related Alterations in Postmortem Brain Tissue of Autism Spectrum Disorder." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/34.

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Autism spectrum disorder (ASD) is a social, sensory and developmental condition that affects one in 59 children and specifically one in 42 boys. Despite the 15% increase in prevalence in the last two years, there is no specific etiology, objective diagnostic criteria, or drug treatment. However, up-regulation of inflammation in ASD patients has been demonstrated in blood samples. Increased peripheral inflammation could have devastating effects on the developing brain. Peripheral inflammation in the blood could cross the blood-brain-barrier to stimulate microglia in the brain to produce aberrant levels of cytokines that regulate neuroinflammation such as insulin-like growth factor one (IGF1) that could alter neuronal cell-surface expression and neurotransmission. Additionally, arginase serves as a marker of inflammation, produced and expressed during cellular remodeling during brain injury. A balance of neurotransmitters, glutamate and gamma-aminobutyric acid (GABA), is critical to facilitate inter-regional signaling in the brain. Alterations of inflammatory molecules and the effects on glutamatergic neurons ability to uptake GABA in certain brain areas is currently unknown in ASD. Pathological changes in brain areas associated with social behaviors have been identified in postmortem tissue from ASD donors when compared to typically developing (TD) age and gender matched control tissue, as well as, in imaging scans of living individuals with ASD. We hypothesize that expression of inflammatory related molecules are increased in the identified brain areas related to symptoms of ASD and can be associated with altered gene expression changes in neurons as shown by gamma-aminobutyric acid type A receptor alpha 1 subunit (GABRA1). Dysfunction of GABRA1 on glutamatergic neurons could disrupt the typical neuronal balance of glutamate and GABA signaling. Inflammatory markers, IGF1 and insulin-like growth factor one receptor (IGF1R), were evaluated using quantitative polymerase chain reaction (QPCR). Additionally, IGF1 and arginase were evaluated using immunohistochemistry in both white and gray matter from the anterior cingulate cortex (ACC). Laser capture microdissection (LCM) was used to obtain single cell captures of glutamatergic neurons. IGF1R and GABRA1 gene expression was measured using end point PCR. A significant increase in IGF1 expression was obtained in the white matter punch in comparison to typically developed age-matched subjects using QPCR during initial statistical significance, however, was ultimately not significant. Additionally, IGF1R expression was significantly increased in ASD neurons in comparison to TD subjects utilizing the LCM method. However, a decrease expression in GABRA1 trended significance indicating a possible alteration in the neuron’s ability to facilitate proper signaling. These findings are the foundation of future investigations of signaling pathways in ASD that may uncover cell-specific etiologies and drug therapies for a condition that is only projected to increase in prevalence.

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Green, Charmaine. "THE ROLE OF INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR SIGNALLING IN THE MOUSE EMBRYO DURING PREIMPLANTATION DEVELOPMENT AND EARLY IMPLANTATION." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/17684.

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The use of assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) is increasing and today close to 4 percent of babies born in Australia, are as a result of ART. IVF procedures involve the culture of resultant embryos in medium that routinely lacks the growth factors that are present in the reproductive tract. Cultured embryos develop at a slower rate and have higher levels of developmental arrest, with fewer than 50% of embryos reaching the blastocyst stage. Furthermore, once an embryo is transferred back into the uterus, it faces the hurdle of implantation, with implantation failure being a major cause of IVF failure. This thesis examines whether the addition of growth factors to the embryo culture medium can increase blastocyst development and adhesion competency, using mouse embryos as a model system. In particular, the effect of insulin-like growth factor 1(IGF1) and insulin-like binding protein 3 (IGFBP3) on preimplantation mouse embryo development in vitro and the role of IGF1 on implantation in vitro was examined. In the present study, the culture of preimplantation embryos in the presence of a physiological concentration of IGF1 improved development from compaction onwards, resulting in improved blastocyst development. Conversely, high levels of IGF1 negatively impacted on development by decreasing hatching probably due to these high levels of IGF1 causing IGF1 receptor (IGF1R) down-regulation and apoptosis in the mouse embryo, as shown previously. Blocking the IGF1R with a neutralising antibody was shown to decrease blastocyst development, hatching and cell numbers and to increase apoptosis. Furthermore, treatment of blastocysts with IGF1 caused phosphorylation of Akt, which regulates cell survival by activating anti-apoptotic pathways. Therefore, IGF1 may act as a survival factor in the preimplantation embryo. During early implantation integrins accumulate on the surface of the blastocyst and endometrium and these interact with each other via extracellular matrix proteins such as fibronectin. These interactions are important for the attachment of blastocysts to the endometrium. In the present study treatment of blastocysts with IGF1 increased fibronectin on the surface of the blastocyst via activation of the Phosphoinositide 3 Kinase (PI3K) pathway. As a result, blastocysts had increased attachment to cultured uterine epithelial cells and increased outgrowth. In addition to IGF1, the reproductive tract produces IGFBP3, which is also thought to improve development of the embryo. However, to the best of our knowledge this is the first study to examine the effect of exogenous IGFBP3 on embryo development in vitro. IGFBP3 caused an increase rate of progression of embryos through the early stages of division (5-8cells) and activation of Akt and ribosomal protein S6 (rpS6) proteins as well as induction of calcium signalling. In the present study, it appears that IGFBP3 signalling in the embryo requires the IGF1R, as the use of an IGF1R neutralising antibody blocked IGFBP3 from enhancing early stages of division and the induction of calcium signalling. In other cell types, IGFBP3 signals through the IGF1R following a transactivation event involving the Sphingosine 1-Phosphate (S1P) pathway. The complex interactions and signalling of IGFBP3 are beginning to emerge in a number of different cell types and further investigation of IGFBP3 function is required in the embryo. As growth factors are generally absent from embryo culture media there is a potential avenue for the improvement of embryo culture and ART outcomes by addition of IGF1 and or IGFBP3 to the culture medium. The requirements of the embryo are complex and understanding the role of growth factors in embryo development is essential in order to optimise embryo culture and develop culture media for use in ART.

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Ratcliffe, Laura. "IGF1 signalling impairment in human astrocytes and the impact on neuronal support." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/16059/.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is classically characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) and research to date has largely focused on how these plaques and tangles affect neuronal function. However, there is evidence to suggest that the fundamental homeostatic support offered by astrocytes may be dysregulated early on in AD progression. Changes in cell signalling, particularly impairments in the insulin/insulin-like growth factor 1 (IGF1) pathway are now widely reported in AD and more recently, alterations to this pathway have been identified in astrocytes. The contribution of impaired insulin/IGF1 signalling in AD is unclear since there is also extensive literature showing an association between dysregulated insulin/IGF1 signalling and longevity. The aim of this thesis is to understand how impaired IGF1 signalling affects the function of human astrocytes and their support for neurons. To achieve this, human astrocytes were treated with a monoclonal antibody (MAB391) that specifically targets insulin-like growth factor 1 receptor (IGF1R), causing downregulation of the receptor. A novel human astrocyte-neuron co-culture was developed to establish a physiologically relevant environment for the astrocytes and so that any alterations in astrocyte neuronal support could be observed. IGF1 signalling impaired astrocytes were less able to support neurons when challenged with hydrogen peroxide, as revealed in a neurite outgrowth assay. Using FACS sorting, astrocytes were enriched from the co-cultures and the transcriptomic profile of MAB391-treated astrocytes was assessed compared to control. Dysregulation in cell pathways involved in astrocyte energy metabolism were identified, with particular defects in complex I activity being validated. Therefore, loss of IGF1R may impair astrocyte energy metabolism and reduce support for neurons in conditions of external stress. This could suggest that therapeutically restoring the IGF1 signalling pathway in astrocytes may preserve support for neurons during ageing and AD-associated stress.

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Coutinho, Debora Cabral. "Estudo do gene do fator de crescimento insulina-símile 1 (IGF1) e de receptor (IGF1R) em crianças nascidas pequenas para a idade gestacional." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-31082009-150428/.

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Crianças nascidas pequenas para a idade gestacional (PIG) apresentam maior risco de permanecerem com baixa estatura na vida adulta. Os fatores de crescimento insulina-símile 1 e 2 (IGF-1 e IGF-2) são os principais fatores endócrinos determinantes do crescimento fetal. Na vida pós-natal o GH, principal hormônio promotor de crescimento, exerce a maior parte de seus efeitos por meio do IGF-1. A grande maioria das ações conhecidas do IGF-1 e IGF-2 são mediadas via receptor tirosina quinase conhecido como receptor tipo 1 de IGFs (IGF-1R). Os objetivos deste trabalho foram estudar os genes IGF1 e IGF1R em crianças nascidas pequenas para a idade gestacional que não recuperaram o crescimento na vida pós-natal. Foram selecionados 145 pacientes nascidos PIG, 72 sem catch up e 73 com catch up. Em 54 PIG sem catch up foi estudado toda a seqüência codificadora do gene IGF1 por meio de PCR e seqüenciamento direto, nos demais PIG sem catch up e nos 73 PIG com catch up foi estudado apenas o exon 6 do IGF-1 por PCR e seqüenciamento direto para avaliação de um polimorfismo encontrado nesta região. Nos pacientes que apresentavam concentração sérica de IGF-1 e IGFBP-3 acima da média para idade e sexo e seqüência do IGF1 normal (n=23) foi realizada coleta de sangue periférico com posterior separação de leucócitos mononucleares pelo gradiente de ficoll seguido por extração de RNA pelo método de Trizol® Posteriormente, a partir do RNA, sintetizamos o cDNA (DNA complementar) utilizando primers randômicos. Foi realizado PCR e seqüenciamento direto do cDNA, além de análise da expressão do IGF1R por PCR em tempo real. Nenhuma mutação foi encontrada no gene IGF1. Entretanto um locus altamente polimórfico foi encontrada na região 3\' não traduzida do exon 6 deste gene, região esta envolvida no processo de poliadenilação. A freqüência das variantes alélicas foi semelhante em PIG com e sem catch-up e em controles nascidos AIG. Analisando o fenótipo de pacientes PIG que apresentavam a variante alélica wild type ou uma das três variantes alélicas mais freqüentemente encontradas, não observamos diferenças significativas entre peso e comprimento ao nascimento, níveis de IGF-1 e crescimento na vida pós-natal. No gene IGF1R encontramos duas variantes alélicas nunca descritas previamente. A primeira variante encontrada está localizada no exon 1, em uma região de peptídeo sinal do pro IGF-1R e consiste na troca do nucleotídeo guanina pelo nucleotídeo adenina na posição 16 da região codificadora (c.16G>A), levando a troca do aminoácido glicina por arginina na posição 6 da proteína (p.G6R). A outra mutação encontrada está localizada no exon 7 onde observamos uma troca do nucleotídeo citosina por timina na posição 1531 do cDNA (c.1531 C>T), levando a uma troca de arginina por triptofano na posição 511 do IGF1R (p.R511W). Adicionalmente, foi observada uma expressão do IGF1R diminuída em 5 pacientes estudados.Concluímos que as variantes alélicas encontradas na região de poliadenilação do IGF1 não influenciam significativamente as características ao nascimento e pós-natais de crianças nascidas PIG ou a altura adulta de indivíduos normais nascidos AIG. O estudo do IGF1R identificou duas novas variantes alélicas em heterozigose no gene IGF1R e, em cinco pacientes, observamos uma expressão reduzida deste gene. Pacientes com alterações no gene IGF1R não apresentam um fenótipo característico que os diferencie de outras crianças nascidas PIG sem alterações neste gene, mostrando a importância dos estudos moleculares.
Children born small for gestational age (SGA) have a higher risk of remaining short in adulthood. The insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) are the main factors determining endocrine fetal growth. GH is the main promoter of linear growth in the postnatal life, exerting its effects mostly through the IGF-1. The vast majority of known actions of IGF-1 and IGF-2 are mediated by the insulin-like growth factor type 1 receptor (IGF-1R), a member of the tyrosine kinase receptors family. The aim of this study was to investigate IGF1 and IGF1R genes mutations in children born small for gestational age without catch up growth in postnatal life. We selected 145 patients born SGA, 72 without catch-up and 73 with catch up. The whole coding region of the IGF1 gene was sequenced in 54 patients without catchup. In the other SGA children without catch-up and in 73 SGA with catch-up, only the exon 6 of IGF1 was sequenced to assess the influence of allelic variants present in this region. In patients with normal IGF1 sequence and IGF-1 and IGFBP-3 serum levels above the mean for age and sex (n = 23) total RNA was extracted from peripheral blood lymphocytes followed by cDNA synthesis with random primers. The IGF1R cDNA was amplified using specific primers followed by direct sequencing. IGF1R expression was analyzed by real-time PCR. No mutations were found in the IGF1 gene. However a highly polymorphic sequence was identified in the upstream core polyadenylation signal (UCPAS) located in IGF1 3\' UTR at exon 6. The frequency of the identified allelic variants was similar in SGA children with and without catch-up and in controls. Furthermore, children homozygous for the wild-type allele and those carrying the allelic variants in homozygous or heterozygous state presented similar weight and length at birth, as well as serum IGF-1 levels and postnatal growth features. Two novel nonconservative allelic variants were identified in IGF1R in 23 SGA children (8.7%) in the heterozygous state. The first variant (c.16G>A) was located in the exon one, leading to a substitution of glicine by arginine in the pro-IGF-1R signaling peptide (p.G6R). The second variant was located in exon 7 (c.1531 C>T), leading to a substitution of arginine by tryptophan in the amino acid 511 of the IGF1-R (p.R511W). Moreover, a decreased IGF1R expression was observed in 5 of the 23 patients with elevated serum IGF-1 concentrations. We conclude that the UCPAS allelic variants did not significantly influence the birth and postnatal characteristics of children born SGA, neither the adult height of normal individuals born adequate for gestational age. The IGF1R study identified two novel allelic variants in two patients and a reduced expression of the IGF1R was observed in five patients. Patients with alterations in IGF1R did not have a distinctive phenotype when compared with other children born SGA without changes in this gene, indicating the importance of molecular studies.

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KERGOSIEN, NATHALIE. "Modulation par l'igf1 du processus de maturation chondrocytaire : etude in vitro." Paris 7, 1999. http://www.theses.fr/1999PA07GA04.

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So, Tammy. "IGF1 and EGF act synergistically to mediate lens fibre differentiation: A process dependent on FGFR-signalling." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/28622.

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Normal lens fibre differentiation is fundamental for maintaining the transparency of the lens and its distinct anatomical polarity. The transition of a lens epithelial cell (“lens stem cell”) into a differentiated lens fibre cell is regulated by growth factors derived from the ocular vitreous media. Growth factors complex with their respective receptor tyrosine kinase receptors to activate signalling pathways [e.g. the extracellular-regulated kinase 1/2 (ERK1/2) and phosphoinositide 3-kinase (PI3K/Akt)] that promote the biochemical and phenotypic changes associated with fibre differentiation. Fibroblast growth factors (FGFs) have been shown to be the primary inducers of lens fibre differentiation. Whilst many other ocular growth factors are involved in this process in vivo, only a high dose of FGF has been demonstrated to initiate this defined differentiation in vitro. Interestingly, a low dose of FGF in combination with another vitreous-derived growth factor such as insulin-like growth factor 1 (IGF1) or epidermal growth factor (EGF) can also stimulate markers of lens fibre differentiation. Using a lens explant culture system, this study demonstrates that IGF1 or EGF can act as a mitogen but not a morphogen on lens epithelial cells. However, for the first time, this study reports that IGF1 in combination with EGF (IGF1/EGF) can act synergistically to induce a fibre differentiation response, resulting in the development of multilayered lentoid bodies, the translocation of Prox1 to the nucleus, and the expression fibre-specific β- and γ-crystallins, independent of exogenously added FGF. Antagonising the FGF receptor (FGFR) could inhibit the IGF1/EGF response and suggests FGFR signalling is involved with the fibre differentiation-like response observed in lens explants co-stimulated with IGF1/EGF. The detection of phosphorylated forms of the downstream FGFR-signalling adaptor protein, fibroblast growth factor substrate 2 alpha (FRS2α), provided further evidence that FGFR signalling is likely implicated in the fibre-specific response mediated by IGF1/EGF. Since FGF-FGFR is the only ligand-receptor couple known to facilitate lens fibre differentiation, possible explanations of the phenomenon may include the transactivation of the FGFR, up-regulation of FGF and/or FGFRs in lens epithelial cells. FGF-FGFR signalling is crucial for the process of fibre differentiation to transpire. Though the present study has established that IGF1/EGF can induce fibre differentiation independent of FGF, the response appears to require FGFR-signalling. Previous studies report that FGF fails to stimulate the appropriate PI3K/Akt signalling profile normally induced by the vitreous. Given this, other endogenous growth factors such as IGF1 and EGF may cross talk to refine the PI3K/Akt signalling pathway by enhancing cell survival and protein biogenesis, which is imperative for maintaining lens transparency and lens cell cytoskeletal integrity.

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Matz-Soja, Madlen, and Rolf Gebhardt. "Hepatic Hedgehog signaling contributes to the regulation of IGF1 and IGFBP1 serum levels." Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-142560.

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Background Hedgehog signaling plays an important role in embryonic development, organogenesis and cancer. In the adult liver, Hedgehog signaling in non-parenchymal cells has been found to play a role in certain disease states such as fibrosis and cirrhosis. However, whether the Hedgehog pathway is active in mature healthy hepatocytes and is of significance to liver function are controversial. Findings Two types of mice with distinct conditional hepatic deletion of the Smoothened gene, an essential co-receptor protein of the Hedgehog pathway, were generated for investigating the role of Hedgehog signaling in mature hepatocytes. The knockout animals (KO) were inconspicuous and healthy with no changes in serum transaminases, but showed a slower weight gain. The liver was smaller, but presented a normal architecture and cellular composition. By quantitative RT-PCR the downregulation of the expression of Indian hedgehog (Ihh) and the Gli3 transcription factor could be demonstrated in healthy mature hepatocytes from these mice, whereas Patched1 was upregulated. Strong alterations in gene expression were also observed for the IGF axis. While expression of Igf1 was downregulated, that of Igfbp1 was upregulated in the livers of both genders. Corresponding changes in the serum levels of both proteins could be detected by ELISA. By activating and inhibiting the transcriptional output of Hedgehog signaling in cultured hepatocytes through siRNAs against Ptch1 and Gli3, respectively, in combination with a ChIP assay evidence was collected indicating that Igf1 expression is directly dependent on the activator function of Gli3. In contrast, the mRNA level of Igfbp1 appears to be controlled through the repressor function of Gli3, while that of Igfbp2 and Igfbp3 did not change. Interestingly, body weight of the transgenic mice correlated well with IGF-I levels in both genders and also with IGFBP-1 levels in females, whereas it did not correlate with serum growth hormone levels. Conclusions Our results demonstrate for the first time that Hedgehog signaling is active in healthy mature mouse hepatocytes and that it has considerable importance for IGF-I homeostasis in the circulation. These findings may have various implications for mouse physiology including the regulation of body weight and size, glucose homeostasis and reproductive capacity.

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Sava, Radović. "Uloga insulinskih i IGF1 receptora u regulaciji steroidogeneze i mitohondrijallne biogenze u Leydigovim ćelijama." Phd thesis, Univerzitet u Novom Sadu, Prirodno-matematički fakultet u Novom Sadu, 2019. https://www.cris.uns.ac.rs/record.jsf?recordId=110282&source=NDLTD&language=en.

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Leydig-ove ćelije testisa su primarno mesto sinteze muških polnih hormona. Ovi hormoni su neophodani za reproduktivno, ali i za opšte zdravlje budući da suozbiljni zdravstveni problemi često povezani sa njihovom smanjenom produkcijom. Insulin i insulinu sličan faktor rasta 1, IGF1 (engl. insulin like growth factor 1), isignalizacija koju pokreću preko svojih receptora (INSR i IGF1R), su jedan od ključnih faktora koji regulišu specifični razvoj tkiva, pa i samih gonada. Ipak, uloga imehanizmi delovanja ovih receptora u steroidogenim tkivima nisu u potpunosti poznati. Stoga je istraživanje uokviru ove doktorske disertacije koncipirano sa ciljem da se, na modelu prepubertalnih (P21) i adultnih (P80) mužjaka miševa sa kondicionalnom delecijom Insr i Igf1r gena u steroidogenim ćelijama (Insr/Igf1r-DKO), definiše uloga INSR i IGF1R u regulisanju diferencijacije i steroidogene funkcije Leydig-ovih ćelija. Pored toga, mužjaci i ženke P21 miševa sa istom delecijom su korišćeni za praćenje ekspresije glavnih markera mitohondrijalne biogeneze i fuzije/arhitekture u Leydigovim ćelijama, ovarijumima i nadbubrežnim žlezdama. Rezultati su potvrdili da delecija Insr i Igf1r usteroidogenim tkivima utiče na diferencijaciju i funkcionalne karakteristike Leydig-ovih ćelija P21 i P80 miševa, upućujući na pojavu tzv. „feminizacije“. BrojLeydig-ovih ćelija izolovanih iz P21 i P80 Insr/Igf1rDKO miševa bio je smanjen, a morfologija i ultrastruktura ovih ćelija izmenjene kod P21 Insr/Igf1rDKO miševa. Steroidogeni kapacitet i aktivnost, kao i ekspresija glavnih elemenata steroidogene mašinerije (Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1 i 6, Hsd17b3,Sf1) bili su smanjeni u Leydig-ovim ćelijama P21 i P80 Insr/Igf1r-DKO miševa, dok je ekspresija transkripcionih represora steroidogeneze (Arr19 i Dax1) bila povećana specifično u istim ćelijama, ali ne i u ostatku testisa.Transkripcioni profil markera muškog pola (Sry, Sox9, Amh) bio je izmenjen u Leydig-ovim ćelijama P21 i P80 Insr/Igf1r-DKO miševa. Transkripcija markera ženskog pola (Rspo1, Wnt4) u testisima, kao i ekspresija Cyp19a1 i produkcija estradiola (E2) u Leydig-ovim ćelijama, P21 i P80 Insr/Igf1r-DKO miševa bile su povećane. Transkripcija markera mitohondrijalne biogenze (Ppargc1a, Tfam, Mtnd1) bila je smanjena u Leydigovim ćelijama P21 Insr/Igf1r-DKO miševa, dok supromene ekspresije izostale u ovarijumima ženki istog genotipa. Isti markeri su bili povećani u nabdubrežnim žlezdama oba pola. Markeri mitohondrijalne fuzije/arhitekture (Mfn1 i Mfn2) bili su povećani u Leydig-ovim ćelijama P21 Insr/Igf1r-DKO miševa, što je praćeno i narušenom mitohondrijalnom fazom steroidogeneze (produkcija progesterona), kao i brojem i morfologijom ovim organela. Ekspresija istih markera u ovarijumima bila je nepromenjena. Sumirano, rezultati ovog istraživanja su pokazali da su INSR i IGF1R važni za diferencijaciju i steroidogenu funkciju Leydig-ovih ćelija P21 i P80 miševa. Takođe, ovi receptori su važni regulatori markera mitohondrijalne biogeneze i fuzije/arhiteture u steroidogenim ćelijama muških gonada P21 miševa, ali ne i u steroidogenim ćelijama ovarijuma.
Leydig cells of testes are the primary site of the male sex hormones synthesis. These hormones are indispensable for both reproductive and general health since serious health problems are often associated with their reduced production. Insulin and insulin-like growth factor 1, IGF1 (insulin like growth factor 1), and signaling triggered through their receptors (INSR and IGF1R), are one of the key factors that regulate specific development of tissue including gonads. However, the role and mechanisms of these receptors action in steroidogenic tissues are not known enough. This study was designed to observe the role of INSR and IGF1R in regulating the differentiation and steroidogenic function of Leydig cells by using the model of prepubertal (P21) and adult (P80) male mice with the conditional deletion of the Insr and Igf1r genes in steroidogenic cells (Insr/Igf1r-DKO). In addition, male and female P21 mice with the samedeletion were used to monitor the expression of the main markers of mitochondrial biogenesis and fusion/architecture in Leydig cells, ovaries and adrenal glands. The results confirmed that deletion of Insr and Igf1r in steroidogenic tissues influences differentiation and functional characteristics of Leydig cells isolated from P21 and P80 mice, suggesting an appearance of "feminization". The number of Leydig cells isolated from both P21 and P80 Insr/Igf1r-DKO mice was reduced. Morphology and ultrastructure of Leydig cells were disturbed in P21 Insr/Igf1r-DKO mice. Steroidogenic capacity and activity, as well as expression of the main elements of steroidogenic machinery (Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd3b1 and 6, Hsd17b3, Sf1) were decreased in Leydig cells from P21 and P80 Insr/Igf1r-DKO mice, while the expression of transcriptional repressors of steroidogenesis (Arr19 and Dax1) was increased in the same cells, but not in the rest of the testes. Transcription profile of the male sex markers (Sry, Sox9, Amh) was altered in Leydig cells from P21 and P80 Insr/Igf1r-DKO mice. Transcription of the female sex markers (Rspo1, Wnt4) in the testes, as well as Cyp19a1 expression and estradiol (E2) production in Leydig cells, from P21 and P80 Insr/Igf1rDKO mice were increased. Transcription of mitochondrial biogenesis markers (Ppargc1a, Tfam, Mtnd1) was declined in Leydig cells from P21 Insr/Igf1r-DKO mice, while changes were absent in the ovaries of the same genotype. Transcription of the same markers was increased in the adrenal glands of both sexes. The mitochondrial fusion/architecture markers (Mfn1 and Mfn2) were increased in Leydig cells from Insr/Igf1r-DKO mice and followed by disturbedmitochondrial phase of steroidogenesis (progesterone production), as well as decreased number and disturbed morphology of mitochondria. Expression of the same markers in the ovaries was unchanged. In summary, results of this study showed that INSR and IGF1R are important in differentiation and steroidogenic function of Leydig cells from P21 and P80 mice. Also, these receptors are important regulators of mitochondrial biogenesis and fusion/architecture markers in steroidogenic cells of P21 male mice, but not in steroidogenic cells of ovaries.

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Coletta, Rocio Riatto Della. "Análise das repetições CA do gene IGF1, VNTR do gene da insulina e região promotora P4 do gene IGF2 em indivíduos nascidos pequenos para idade gestacional." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-29042008-144128/.

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Introdução: Polimorfismos na região promotora dos genes da insulina, IGF2 e IGF1 podem estar relacionados a uma diminuição da expressão desses genes na vida fetal que, por sua vez, pode causar restrição do crescimento intra-uterino e maior risco de hipospádia. Na vida pós-natal, perda completa ou parcial da expressão desses genes pode resultar em ausência de recuperação estatural e menores concentrações séricas de IGF1 na criança, além de um maior risco de diabetes melito tipo 2 e síndrome de resistência à insulina no adulto. Objetivos: Analisar em crianças nascidas pequenas para idade gestacional (PIG) com ou sem recuperação estatural (RE): 1) a freqüência alélica e genotípica dos polimorfismos VNTR-INS e das repetições CA do gene IGF1; 2) a região promotora P4 do gene IGF2; 3) a influência do VNTR INS e das repetições CA do gene IGF1 na sensibilidade à insulina e nas concentrações séricas de IGF1, respectivamente. Pacientes: Foram estudados 142 indivíduos nascidos PIG com (n= 66) e sem recuperação (n= 76) estatural selecionados de três diferentes centros (HC-FMUSP, Santa Casa de São Paulo e HC-UFPR) e um grupo controle constituído de 297 indivíduos nascidos adequados para idade gestacional (AIG). Métodos: Extração de DNA genômico; amplificação por PCR das regiões contendo os polimorfismos VNTR INS e repetições CA do IGF1 e da região promotora P4; digestão por enzima de restrição; software Genescan; seqüenciamento automático; avaliação bioquímica e hormonal da glicemia, insulina e IGF1, extração de RNA, PCR em tempo real e análise estatística com SPSS 13.0 (Statistical Package fo Social Sciences). Resultados: A média do Z-altura, Z-IMC (índice de massa corpórea), Z-altura paterno e ZEA (estatura alvo) foram maiores nas crianças PIG que tiveram recuperação estatural, com o Z-PC (perímetro cefálico) maior nas crianças sem recuperação estatural. O Z-IGF1 sérico foi significantemente mais elevado em crianças que apresentaram RE (p<0,05). A distribuição e genotipica das repetições CA do gene IGF1 e do VNTR INS foi semelhante estatisticamente entre os grupos AIG e PIG, e entre os PIG com e sem RE; não foi observada associação entre esse polimorfismo e as variáveis clínicas e laboratoriais do estudo. O estudo da região promotora P4 do gene IGF2 identificou um novo polimorfismo de 9-12 repetições C na posição -1982, antes do sítio de início de transcrição do exon 2, e este apresentou distribuição semelhante entre os grupos PIG e AIG. Foi identificada também uma troca C/T em heterozigose no nono nucleotídeo do alelo 11C em quatro crianças nascidas PIG. Contudo, a quantificação da expressão do gene IGF2 em duas dessas crianças não demonstrou perda da expressão desse gene. Conclusões: Não observamos influência dos polimorfismos acima descritos no crescimento pré e pós-natal, na presença de resistência à insulina, nem em concentrações séricas de IGF1 dos indivíduos nascidos PIG. Identificamos uma nova variante na região promotora P4 do gene IGF2, contudo estudos preliminares não demonstraram influência desse polimorfismo sobre o crescimento intra-uterino.
Introduction: Polymorphisms in the promoter region of insulin (INS), IGF2 and IGF1 genes may decrease their expression during fetal life and afterward could be related to intra-uterine fetal growth retardation and greater risk of hypospadia development. In post-natal life, decreased expression of these genes can result in lack of stature recovery and in lower IGF1 serum levels in children, as well as in higher risk for type 2 diabetes mellitus and metabolic syndrome in adults. Objectives: The aims of the present study were: (1) to analyze the allelic and the genotypic frequency of the insulin (INS) gene variable number of tandem repeats (VNTR) and the IGF1 gene CA repeats; (2) to analyze the P4 promoter region of IGF2 gene (3) to test the contribution of INS VNTR, IGF1 gene CA repeats on insulin sensitivity and IGF1 serum levels in children born SGA with and without catch up, respectively. Patients: We studied 142 individuals born SGA with catch up (n = 66) and without catch up (n = 76) selected from three different centers (HCFMUSP, Santa Casa de Sao Paulo and HC-UFPR). The control group consisted of 297 children born appropriate for gestational age (AGA). Methods: Extraction of genomic DNA, PCR-amplification of the VNTR of insulin gene, CA repeats of IGF1 and IGF2 gene P4 promoter region; restriction analysis; Genescan software; automatic sequencing. Blood measurements of serum level of glucose, insulin and IGF1. Statistical analysis (Statistical Package for Social Sciences software). Results: Regarding birth parameters, the average of Z-height, Z-BMI (body mass index) and Z-height paternal and Z- EA (target height) were higher in children born SGA who had catch up. Interestingly, we observed that the Z-PC was higher in children born SGA without catch up. In addition, the Z-IGF1 serum levels were significantly higher in children who had catch up (p <0.05). The molecular analysis of IGF1 gene CA repeats and of INS gene VNTR locus did not show a statistically significant difference in the allelic and genotypic distribution of these polymorphisms between adequate for gestational age (AGA) and SGA groups nor between SGA with and without catch up. Similarly, we have not found an association of these polymorphisms with clinical or laboratory variables of this study. A novel polymorphism in the P4 promoter region of the IGF2 gene was identified. It was characterized by cytosine repeats (9-12) at position -1982 before transcription initiation site of exon 2 of IGF2 gene. Yet, we have identified a heterozygous substitution of cytosine for thymine at the nucleotide position 9 in the allele 11C in four children born SGA. This change was also absent in the control population. Quantization of IGF2 gene expression in two of these children did show loss of expression of this gene in patients carrying the variant 9C/T. Conclusions: We have not observed an association of the above described polymorphisms with pre and post natal growth, or with the occurrence of insulin resistance in individuals born SGA. IGF-1 levels did not seem to be associated with the polymorphisms either. A new variant in the P4 promoter region of IGF2 gene was identified, however preliminary studies showed no influence on intra-uterine growth.

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Drost, Adriana C. "The functions of growth factors in pituitary tumors and their effect on IGF1 receptor regulation." [S.l.] : [s.n.], 2002. http://www.diss.fu-berlin.de/2002/286/index.html.

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Cookman, Clifford. "Characterization of 17ß-Estradiol Survival Signaling in Medulloblastoma: Relation to Tumor Growth and IGF1 Signaling." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158097.

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Song, Jin H., Sathish K. R. Padi, Libia A. Luevano, Mark D. Minden, Daniel J. DeAngelo, Gary Hardiman, Lauren E. Ball, Noel A. Warfel, and Andrew S. Kraft. "Insulin receptor substrate 1 is a substrate of the Pim protein kinases." IMPACT JOURNALS LLC, 2016. http://hdl.handle.net/10150/614947.

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The Pim family of serine/threonine protein kinases (Pim 1, 2, and 3) contribute to cellular transformation by regulating glucose metabolism, protein synthesis, and mitochondrial oxidative phosphorylation. Drugs targeting the Pim protein kinases are being tested in phase I/II clinical trials for the treatment of hematopoietic malignancies. The goal of these studies was to identify Pim substrate(s) that could help define the pathway regulated by these enzymes and potentially serve as a biomarker of Pim activity. To identify novel substrates, bioinformatics analysis was carried out to identify proteins containing a consensus Pim phosphorylation site. This analysis identified the insulin receptor substrate 1 and 2 (IRS1/2) as potential Pim substrates. Experiments were carried out in tissue culture, animals, and human samples from phase I trials to validate this observation and define the biologic readout of this phosphorylation. Our study demonstrates in both malignant and normal cells using either genetic or pharmacological inhibition of the Pim kinases or overexpression of this family of enzymes that human IRS1S1101 and IRS2S1149 are Pim substrates. In xenograft tumor experiments and in a human phase I clinical trial, a pan-Pim inhibitor administered in vivo to animals or humans decreased IRS1S1101 phosphorylation in tumor tissues. This phosphorylation was shown to have effects on the half-life of the IRS family of proteins, suggesting a role in insulin or IGF signaling. These results demonstrate that IRS1S1101 is a novel substrate for the Pim kinases and provide a novel marker for evaluation of Pim inhibitor therapy.

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Barbaro, Barbara, and Barbara Barbaro. "'VALUTAZIONE DEL RUOLO E DEL MECCANISMO DI AZIONE DEL VEGF (VASCULAR ENDOTHELIAL GROWTH FACTOR) SULLE CELLULE DELL'ALBERO BILIARE INTRAEPATICO' II parte: 'STUDIO DI IGF1 ED ESTROGENI COME BASE PER L'INDIVIDUAZIONE DI UNA INTERAZIONE IGF1 EE - VEGF NELLA MODULAZIONE DEL COLANGIOCARCINOMA'." Doctoral thesis, La Sapienza, 2006. http://hdl.handle.net/11573/916927.

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Sarem, Mahrou. "Identification dans les sérums de mammifères de peptides (MW< 1000 DA) à activité mitogénique : influence de ces peptides sur les activités biologiques des IGF1 et IGF2." Nancy 1, 2000. https://hal.univ-lorraine.fr/tel-01746897.

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Thèse de doctorat en génie biologique et médical. Les facteurs de croissance de petit poids moléculaire qui ont été identifiées dans le sérum humain par leur capacité à stimuler des activités biologiques des IGFs (insulin-like growth factors), et en particulier deux peptides (HWESAS et WGHE), représentent une nouvelle voie d'étude des facteurs de croissance. L'objectif de ce travail a été initialement de rechercher la présence de ces petits peptides (MM<1000 Da) dans le sérum de certains mammifères. Les ultrafiltrats provenant de sérum de cheval, porc, boeuf et souris exercent un effet potentialisateur sur l'activité mitogénique des IGFs. Cet effet peut s'expliquer en partie par la présence de HWESAS dans les sérums à des concentrations variant de 2 à 28 mg/L. Dans la seconde partie, nous nous sommes intéressés aux activités mitogéniques de HWESAS et de peptides dérivées sur différentes lignées cellulaires. Ces peptides ont une activité mitogénique propre et modulent celle des IGFs. Cette activité mitogénique pourrait faire intervenir des isoformes de la PKC (étude sur les fibroblastes d'embryons de poulets). HWESAS agit en synergie avec les acides aminés dans les cellules ou la stimulation de la synthèse protéique. De plus il agit en synergie avec les IGFs pour augmenter la phosphorylation des protéines. L'étude du cycle cellulaire ainsi que la mesure de la fixation de l'annexine V-FITC, montrent que HWESAS seul ne protège pas des fibroblastes d'embryons de poulets contre l'apoptose, mais associé aux IGFs il exerce un certain effet protecteur.

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Naville, Danielle. "Purification et caractérisation partielles d'une protéine liant IGF1 et appartenant au complexe de 145K circulant dans le plasma humain : étude de son activité biologique sur les cellules de Leydig de porc immature en culture en présence de IGF1." Lyon 1, 1988. http://www.theses.fr/1988LYO1T120.

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Naville, Danielle. "Purification et caractérisation partielles d'une protéine liant IGF1 et appartenant au complexe de 145K circulant dans le plasma humain étude de son activité biologique sur les cellules de Leydig de porc immature en culture en présence de IGF1 /." Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37616784t.

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Reckenbeil, Jan [Verfasser]. "Die Wirkung von IGF1 auf Zellen des parodontalen Ligaments unter Einfluss von Hypoxie und Entzündung / Jan Reckenbeil." Bonn : Universitäts- und Landesbibliothek Bonn, 2012. http://d-nb.info/1044082844/34.

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Ouni, Meriem. "Relation entre la méthylation des promoteurs du gène IGF1 et les variations de la croissance des enfants." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T015/document.

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A l'interface de la génétique et de l'environnement, l'épigénétique contribue à la diversité phénotypique. Déterminer l'impact de la variation épigénétique sur les caractères quantitatifs (QT) est un nouveau défi. La croissance staturale fournit l’opportunité d’étudier la variabilité de plusieurs traits phénotypiques liés entre eux : des QT cliniques (la taille, l’accélération de la vitesse de croissance en réponse à l'hormone de croissance, GH) et des QT biologiques tels que la concentration d’IGF1 et la réponse de cette concentration à la GH. L’ « Insulin-like Growth Factor 1 » (IGF1) contrôle la croissance postnatale chez les mammifères, y compris l'homme. Nous l’avons choisi comme locus candidat pour nos études épigénétiques. Nous avons quantifié la méthylation des deux promoteurs P1 et P2 de ce gène, qui régulent son expression. Notre objectif était d’évaluer la contribution de la méthylation d’ADN de ces promoteurs i) à la taille des enfants en croissance, ii) à l’IGF1 circulant, iii) et à la réponse de ces paramètres à un traitement par la GH. Taille et IGF1 circulant. La relation entre la méthylation des promoteurs d’IGF1 et la taille a été étudiée au sein de deux cohortes du service d'endocrinologie pédiatrique, totalisant 216 enfants prépubères de différentes statures. Nous avons montré que la méthylation d'un groupe de six CGs situés dans la partie proximale du promoteur P2 du gène IGF1 présentait une corrélation inverse avec la croissance et l'IGF1 circulant. Les enfants les plus grands sont ainsi moins méthylés sur ces CGs que les enfants de petite taille. La contribution de la méthylation à la variance de la taille a été évaluée à environ 13%, et à 10% pour la variance de l'IGF1 sérique. Pour montrer que l’association observée reflète une causalité biologique, nous avons étudié le lien entre la méthylation des promoteurs P1 et P2 et l'activité transcriptionnelle du gène IGF1 in vivo et in vitro. Nous avons montré que les quantités de transcrits de classe II, issus du promoteur P2, sont inversement corrélés à la méthylation du promoteur P2 dans les cellules sanguines mononucléées. In vitro, nous avons cloné le promoteur P2 déméthylé ou méthylé dans un plasmide rapporteur (luciferase) transfecté dans la lignée HEK293 : le promoteur déméthylé s’est révélé nettement plus actif (+57%). Finalement, nous suggérons que l’hyperméthylation de certains CGs du P1 et du P2 d’IGF1 pourrait être un des nombreux mécanismes moléculaires responsables d’une moindre expression du gène et d’un phénotype de petite taille. La réponse au traitement par la GH. Une fraction des enfants de petite taille est traitée par l'hormone de croissance (GH) pour accélérer sa croissance, mais l’efficacité du traitement est très variable entre les individus. Les causes de cette variabilité sont partiellement comprises : la génétique joue un rôle, mais il reste une place possible pour la variabilité épigénétique. Dans ce but, nous avons étudié l'effet direct de la variabilité épigénétique sur la transcription du gène IGF1 et l’IGF1 circulant, dans un test aigu d’administration de GH, puis sur la réponse thérapeutique à un traitement d’un an par la GH. Après une injection de GH, nous avons constaté une augmentation variable du nombre de transcrits d’IGF1 chez les enfants étudiés. L'augmentation des transcrits de la classe II était inversement corrélée à la méthylation des CGs du P2. La variabilité de méthylation au CG-137 contribuait pour 20% à 67% de l’expression d’IGF1 en réponse à la GH. Chez 136 enfants de petite taille, nous avons montré que la méthylation de l'ADN du promoteur P2 était associée à la réponse au traitement par la GH au cours de la première année. Cette association est observée pour l'augmentation de la vitesse de croissance et pour les taux d’IGF1. (...)
At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits (QT), an emerging challenge in humans. Growth provides a handset of quantitative traits to epigenetic studies. We studied the variability of several inter-related QTs: clinical QTs (height, height reponse to growth hormone and biological QT (serum IGF1 and serum IGF1 response to GH). Since insulin-like growth factor 1 (IGF1) controls postnatal growth in mammals including human, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene could be a epigenetic contributor to the individual variation i) in circulating IGF1 and stature in growing children. ii) on response of these parameters to treatment with (GH). Child height and circulating IGF1. To explore the relation between IGF1 promoter methylation and height, we studied two cohorts of pedriatric endocrinology department, totalling 216 prepubertal children with various statures. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. These correlations were observed in two cohorts of growing children. Tall children show lower levels of methylation in several CGs in P2 and P1 promoters of IGF1 gene than short children with idiopathic short stature. CG methylation contributed 13% to the variance of height and 10% to the variance of serum IGF1. To test if the found association reflected biological causality, we tested if methylation at the P2 promoter affects the transcriptional activity of the IGF1 gene. The transcriptional activity of the P2 promoter was inversely correlated with the CG methylation in mononuclear blood cells. We established that high levels of CG methylation at the two promoters of IGF1 contributed to the many molecular mechanisms responsible for “idiopathic” short stature. Response to treatment with (GH). Short children using growth hormone (GH) to accelerate their growth respond to this treatment with a variable efficacy. The causes of this individual variability are partially understood and could involve epigenetics. In this aim, we investigated the contribution of DNA methylation to the response to GH at two levels: direct effect of GH on transcription of IGF1 gene, on circulating IGF1 and on the growth response to GH. Following a GH injection, we found a variable increase in IGF1 transcripts across the studied children. The increase in P2-driven transcripts showed a strong inverse correlation with 4/8 of P2 CGs. Among the CGs of P1 promoter, only CG-611 showed an inverse correlation with P1-driven transcripts. Variability of DNA methylation in these CGs contributes with 27% to 67% of increase in transcripts. In 136 children with idiopatic short stature, we showed that DNA methylation of the P2 promoter is associated with growth response to GH during the first year of GH administration, for both increment in growth rate and circulating IGF1. CG-137 methylation of P2 promoter contributes 25% to variance of growth response to GH. The link between DNA methylation and the response to a treatment in humans illustrating the role of epigenetic marks as potent contributors to conclusion « pharmacoepigenetics». Our work can find application in growth physiology and therapeutics, as well as for studies in aging, longevity or cancer where IGF1 has a prominent role

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Barnes, Brian R. "The effects of a glucocorticoid-antagonist on IGF1-stimulated glucose uptake in skeletal muscle of hindlimb suspended rats." Virtual Press, 2000. http://liblink.bsu.edu/uhtbin/catkey/1164845.

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The Effects of a glucocorticoid-antagonist on IGF1-stimulated glucose uptake in skeletal muscle of hindlimb suspended rats. Barnes B.R., T.C. Selix, D.C. Wright, and B.W. Craig. Ball State University, Muncie, IN.The purpose of this investigation was to determine the effects of a glucocorticoid-antagonist (RU486) on insulin-like-growth-factor-1 (IGF1)stimulated glucose transport following two weeks of hindlimb suspension (HS) on 100 gm male rats. After two weeks of HS and/or oral RU486 administration the animals were anesthetized, and the soleus (SOL) and extensor digitorum longus (EDL) muscles isolated and clamped at their resting length. Following an incubation series to prepare the muscle, the muscle was incubated in radioactive 3-O-methylglucose for 10 min. in the presence/absence of 75 ng/ml of IGF1, digested with 0.5 NaOH, and the amount of glucose transported measured. Two weeks of RU486 treatment significantly (P:5 0.05) elevated IGF1-stimulated glucose transport of SOL (0.576 ± 0.071 vs 1.405 ± 0.172), whereas the EDL was unaffected (2.728 0.258 vs 2.613 ± 0.182). The removal of glucocorticoids via RU486 administration significantly increased glucose uptake in HS exposed soleus muscles. The EDL was not affected by RU486 treatment.
School of Physical Education

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Reis, Vania Marisia Santos Fortes dos. "Análise de expressão gênica da via de sinalização do receptor do fator de crescimento semelhante à insulina tipo 1 no câncer de endométrio." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2018. http://hdl.handle.net/10183/178366.

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O câncer de endométrio tem incidência crescente, principalmente nos países desenvolvidos, devido ao estilo de vida moderno, aumento de casos de obesidade e diabetes, e diversos outros fatores que, em conjunto, estão tornando esta neoplasia na mais comum no trato reprodutor feminino. Ele é bastante influenciado pelo estado hormonal e por fatores reprodutivos das pacientes. Assim, é mais frequente no período pós-menopausa, quando pode ocorrer um desequilíbrio na sinalização do estrogênio. A diabetes e a obesidade são causadas, principalmente, pelo excesso de triglicerídeos e glicose circulantes, e pela resistência à insulina. A hiperglicemia leva à produção excessiva de insulina e do fator de crescimento semelhante à insulina tipo 1 (IGF1), sendo que estes hormônios são considerados antiapoptóticos e promotores da proliferação celular. Sabe-se que eles agem por vias semelhantes e que, provavelmente, o mecanismo responsável pela proliferação provocada por eles está associado à via PI3K/Akt/mTOR. Desta forma, avaliamos a expressão gênica de 92 genes na rota de sinalização do IGF1R em câncer de endométrio (n=3) e endométrio normal (n=2), através da técnica de qRT-PCR (ensaio TaqMan® Array Human IGF1R Signaling). Dentro destes genes, alguns estão envolvidos diretamente com a via PI3K/Akt/MAPK, outros estão implicados em processos como proliferação, diferenciação, tumorigênese, apoptose, resposta imune, síntese proteica, entre outros. Avaliamos, também, os níveis proteicos do receptor do fator de crescimento semelhante à insulina (IGF1R), IGF1 e receptor da insulina (IR) pela técnica de imunohistoquímica, além da funcionalidade geral dos 4 genes mais diferencialmente expressos no câncer de endométrio Observamos que, dos 92 genes, 26 foram expressos somente no grupo câncer - CACNA1H, CRK, EIF2B5, ELK1, FRAP1 (MTOR), GYS1, HRAS, IGF2, IKBKB, IKBKE, ITPR3, KRAS, NFAT5, NFATC1, NFKB1, NFKBIB, NFKBIE, PIK3CA, PIK3CB, PLCB1, PLCB2, PLCG2, PRKCZ, RELB, SHC1 e YWHAZ; 46 tiveram expressão aumentada no grupo câncer de endométrio - AKT1, AKT2, ARAF, ATF4, BAD, BRAF, CACNA1C, CALM1, CALM2, CALM3, CREB1, EIF4E, FOXO3, GSK3B, IGF1, IGF1R, IKBKG, IRS1, MAP2K1, MAP2K2, MAPK3, MEF2C, MEF2D, NFATC2, NFATC3. NFKB2, NFKBIA, NRAS, PDPK1, PIK3CD, PIK3R1, PIK3R2, PLCG1, PPP3CA, PPP3R1, PRKCI, RAF1, RAPGEF1, RELA, RPS6, RPS6KB1, SOS1, YWHAB, YWHAE, YWHAH e YWHAQ, um não apresentou expressão em nenhum dos grupos (SLC2A4) e não foi possível analisar os restantes 20 genes, pois não foram expressos em todas as amostras. Quanto à expressão das proteínas IGF1R, IGF1 e IR, todas se mostraram mais expressas no câncer de endométrio e que se encontram localizadas principalmente no citoplasma das células. Assim, este trabalho mostra que a sinalização do IGF1R pode ter participação importante na aquisição do fenótipo maligno das células endometriais, e que o aumento das moléculas efetoras desta via no câncer de endométrio provavelmente está relacionado ao seu papel mitogênico.
Endometrial cancer has a growing incidence, especially in developed countries, because of the modern lifestyle, increased cases of obesity and diabetes, and several other factors that together make this disease the most common in the female reproductive tract. Endometrial cancer is strongly influenced by the hormonal state and by the reproductive factors of the patients. Thus, it is attributed to the postmenopausal period, when estrogen signaling can be unbalanced, and consequently lead to malignant proliferative patterns. Diabetes and obesity are caused mainly by the excess of circulating triglycerides and glucose, and by insulin resistance. Hyperglycemia leads to excessive production of insulin and IGF1.These hormones are considered to have antiapoptotic effects and to promote cell proliferation. It is known that they are very similar pathways, and the mechanism responsible for this proliferation is associated with the PI3K/Akt/mTOR pathway. Thus, we evaluated the expression of 92 genes in IGF1R signaling pathway in endometrial cancer (n = 3) and normal endometrium (n = 2), using qRT-PCR (TaqMan® Array Human IGF1R Signaling test). Within these genes, some are in the PI3K/Akt/MAPK pathways, others are involved in proliferation, differentiation, tumorigenesis, apoptosis, immune response, protein synthesis, among others We also evaluated the protein levels of IGF1R, IGF1 and IR by immunohistochemistry, as well as the general functionality of the 4 most differentially expressed genes in endometrial cancer. We found that 26 genes were expressed only in endometrial cancer - CACNA1H, CRK, EIF2B5, ELK1, FRAP1 (mTOR), GYS1, HRAS, IGF2, IKBKB, IKBKE, ITPR3, KRAS, NFAT5, NFATc1, NFKB1, NFKBIB, NFKBIE, PIK3CA, PIK3CB, PLCB1, PLCB2, PLCG2, PRKCZ, RELB, SHC1 and YWHAZ; 46 had increased expression in endometrial cancer, when compared to control group - AKT1, AKT2, ARAF, ATF4, BAD, BRAF, CACNA1C, CALM1, CALM2, CALM3, CREB1, eIF4E, FOXO3, GSK3B, IGF1, IGF1R IKBKG, IRS1, MAP2K1, MAP2K2, MAPK3 , MEF2C, MEF2D, NFATC2, NFATC3. NFKB2, NFKBIA, PIK3R1, PIK3R2, PLCG1, PPP3CA, PPP3R1, PRKCI, RAF1, RAPGEF1, RELA, RPS6, RPS6KB1, SOS1, YWHAB, YWHAE, YWHAH and YWHAQ, one showed no expression in neither groups (SLC2A4) and the other 20 were not expressed in all samples, so we decided not to analyze them. As for the expression of IGF1R, IGF1 and IR proteins, all them showed increased expression in endometrial cancer and were localized in the citoplasm. Thus, this work shows that IGF1R signaling may play an important role in the acquisition of a malignant phenotype by endometrial cells, and that the increase of these effectors in endometrial cancer is related to its mitogenic effects.

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Hack, Nicole L. "The Insulin-Like Growth Factor-1 (IGF1) System as a Potential Biomarker for Nutritional Status and Growth Rate in Pacific Rockfish (SEBASTES SPP.)." DigitalCommons@CalPoly, 2017. https://digitalcommons.calpoly.edu/theses/1824.

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Growth performance in vertebrates is regulated by environmental factors including the quality and quantity of food, which influences growth via endocrine pathways such as the growth hormone (GH) / insulin-like growth factor somatotropic axis. In several teleost fishes, circulating concentrations of insulin-like growth factor-1 (Igf1) correlate positively with growth rate, and it has been proposed that plasma Igf1 levels may serve as an indicator of growth variation for fisheries and aquaculture applications. Here, I tested whether plasma Igf1 concentrations might serve as an indicator of somatic growth in olive rockfish (Sebastes serranoides), one species among dozens of rockfishes important to commercial and recreational fisheries in the Northern Pacific Ocean. I reared juvenile olive rockfish under food ration treatments of 1% or 4% wet mass per d for 98 d to experimentally generate variation in growth. Juvenile rockfish in the 4% ration grew 60% more quickly in mass and 22% faster in length than fish in 1% ration. Plasma Igf1 levels were elevated in rockfish under the 4% ration, and individual Igf1 levels correlated positively with growth rate, as well as with individual variation in hepatic igf1 mRNA levels. These data in olive rockfish support the possible use of plasma Igf1 as a positive indicator of growth rate variation in rockfishes. Using my findings from this experiment, I further investigated the use of this biomarker in wild rockfish by examining patterns of Igf1 variation in blue rockfish (Sebastes mystinus) caught within and outside of two Marine Protected Areas (MPAs) along California’s coast: Piedras Blancas MPA and Point Buchon MPA. Individual Igf1 levels correlated positively with increasing size as seen in laboratory reared fish. After correcting plasma Igf1 values for body size, circulating Igf1 was observed to be higher in blue rockfish within the boundaries of the Piedras Blancas MPA compared to fish from an adjacent site with no fishing restrictions. Igf1 levels in blue rockfish caught within the Point Buchon MPA, however, were similar to those outside of that MPA. These results suggest that blue rockfish within the Piedras Blancas MPA may experience enhanced growth relative to conspecifics outside of that MPA’s boundaries, and that such growth increases may be specific to MPA locations. My findings support previous studies that Igf1 is a positive indicator for growth in teleost fish and can be used as a tractable biomarker in wild rockfish which could enhance management efforts of fish stocks within marine protected areas.

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Firmenich, Caroline Susanne [Verfasser]. "Effects of dietary nitrogen and / or calcium on renal calcium and phosphate transport and modulation of calcitriol- and IGF1-synthesis in young goats / Caroline Susanne Firmenich." Hannover : Stiftung Tierärztliche Hochschule Hannover, 2019. http://d-nb.info/1189654636/34.

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35

Souza, Luiz Waldemar de Oliveira. "Efeitos da somatotropina recombinante bovina sobre as características espermáticas, concentrações de testosterona e IGF1 no plasma seminal de touros (Bos taurus taurus) submetidos à degeneração testicular." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/10/10131/tde-06072005-141136/.

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Dentre os diversos fatores que provocam diminuição no desempenho reprodutivo, a degeneração testicular térmica é o motivo mais freqüente de baixa fertilidade em Bos taurus no Brasil. Baseados nos efeitos sobre a secreção de hormônios hipofisários e gonadais, o GH vem sendo estudado para o tratamento da infertilidade masculina. Um delineamento experimental tipo blocos ao acaso utilizou dezesseis touros adultos submetidos a 4 tratamentos em esquema fatorial 2x2 (0 e 96 horas de insulação testicular, 0 e 1,2 mg bST/kg PV), com o objetivo de testar os efeitos da bST no tratamento de touros submetidos a insulação testicular. Motilidade, alterações de acrossoma, defeitos de cauda e cabeça, gota protoplasmática proximal e defeitos espermáticos totais aumentaram em conseqüência da insulação testicular. As concentrações seminais de Testosterona foram temporariamente diminuídas em resposta a insulação testicular. A ocorrência de gota protoplasmática distal, anomalias de peça intermediária e concentrações seminais de IGF1 não foram afetadas pela insulação testicular. A somatotropina recombinante bovina não afetou as características espermáticas ou concentrações seminais de Testosterona e IGF1.
Testicular heat degeneration is the most common cause of poor fertility of Bos taurus bulls in the tropics. The Growth Hormone has been studied in man infertility treatment with some progress. A randomly blocks experimental design used 16 mature bulls allotted in 4 treatments in a 2x2 factorial arrangement (0 e 96 hours of scrotal insulation, 0 e 1,2 mg bST/kg BW) was performed to asses the effects ob bulls submitted to scrotal insulation. Motility, abnormal acrosome, tail and head defects, proximal droplet, and abnormal sperm increased, and seminal plasma Testosterone was temporally increased in response to scrotal insulation. Distal droplet, midpiece and seminal plasma IGF1 were not affected by bST. The bST did not affect sperm characteristics or seminal Testosterone and IGF1.

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36

Rocha, Erika Dantas de Medeiros. "Efeitos da suplementa??o oral de zinco sobre o crescimento de crian?as pr?-p?beres saud?veis e eutr?ficas." Universidade Federal do Rio Grande do Norte, 2014. http://repositorio.ufrn.br/handle/123456789/19528.

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Introdu??o: o zinco ? um importante micronutriente para numerosos processos bioqu?micos em animais e humanos, desempenhando papel de destaque no crescimento e desenvolvimento. Em popula??es mundiais, a defici?ncia prim?ria grave de zinco n?o ? comum, embora, a defici?ncia leve seja bastante prevalente. Considerando que o zinco ? essencial para a sa?de humana e regula o sistema hipot?lamo, hip?fise, f?gado e osso, buscamos averiguar os seus efeitos no eixo GH-IGF1-IGFBP3 agudamente, mediante administra??o intravenosa com o elemento zinco, e cronicamente, mediante suplementa??o oral com o elemento zinco, usando doses fisiol?gicas de 0.06537 mg Zn/kg (via intravenosa) e 10 mg Zn/dia (via oral). A inclus?o de crian?as pr?-p?beres aparentemente saud?veis e eutr?ficas sem defici?ncia de zinco ? raro na literatura, pois grande parte das publica??es foram reportadas em crian?as apresentando defici?ncia de zinco. A metodologia aplicada foi absolutamente inovadora e original, tornando o estudo altamente relevante para a interface entre endocrinologia e nutri??o. Objetivo: investigar os efeitos da suplementa??o oral e administra??o intravenosa com o elemento zinco sobre a secre??o de GH, IGF1, IGFBP3, OCN, ALP, TRAP e PT em crian?as aparentemente saud?veis e eutr?ficas sem defici?ncia de zinco. M?todos: o estudo foi conduzido durante um per?odo de tr?s meses, e caracterizado por ser randomizado controlado triplo cego. As crian?as foram selecionadas por amostragem n?o probabil?stica de conveni?ncia, provenientes de escolas p?blicas municipais, de ambos os g?neros, na faixa et?ria compreendida entre 8 e 9 anos de idade, divididas em grupo controle (20 crian?as recebendo solu??o placebo contendo 10% de sorbitol) e grupo experimental (20 crian?as suplementadas com o elemento zinco na forma de sulfato de zinco heptahidratado ? ZnSO4.7H2O). As crian?as foram submetidas ? suplementa??o oral de zinco elementar (10 mg Zn/dia) e ? administra??o intravenosa de zinco (0.06537 mg Zn/kg de peso corporal), na forma de ZnSO4.7H2O, cujas amostras sangu?neas foram coletadas em 0, 60, 120, 180 e 210 minutos. Foram realizadas avalia??es antropom?tricas e diet?ticas e dosagens bioqu?micas e hormonais nas crian?as estudadas. Resultados: ap?s a suplementa??o oral, foi observado no grupo experimental (i) aumento significativo dos valores de ingest?o de energia total, prote?na e gordura total (p = 0.0007, p< 0.0001, p< 0.0001, respectivamente), (ii) aumento significativo do zinco s?rico basal (p< 0.0001), aumento significativo das concentra??es plasm?ticas de fostatase alcalina (p = 0.0270), e (iv) correla??o positiva com o IGF1, IGFBP3, OCN, comparando antes e ap?s a suplementa??o (p = 0.0011, p< 0.0001, p< 0.0446, respectivamente). Durante a administra??o venosa de zinco, as concentra??es plasm?ticas de IGF1 e IGFBP3 aumentaram significativamente no grupo experimental (p = 0.0468, p < 0.0001, respectivamente). Em rela??o o c?lculo da adequa??o aparente, segundo as DRI, para o c?lcio, houve inadequa??o da dieta com 85% de confiabilidade dos dados; para o ferro, adequa??o da dieta, com 85% de confiabilidade dos dados. Para o zinco, adequa??o da dieta, com 50% de confiabilidade dos dados. Conclus?es: a suplementa??o oral com o elemento zinco pode ter estimulado um aumento na ingest?o de energia total, prote?na e gordura total, assim como, nas concentra??es basais de zinco s?rico e nas concentra??es plasm?ticas de fosfatase alcalina. A administra??o intravenosa de zinco aumentou as concentra??es s?ricas de zinco e as concentra??es plasm?ticas de GH, IGF1 e IGFBP3 no grupo experimental.

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Eddiry, Sanaa. "Rôle du SNORD116 et de l'IGFBP7 dans la réponse à l'IGF1 dans le syndrome de Prader-Willi." Toulouse 3, 2013. http://www.theses.fr/2013TOU30215.

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Le syndrome de Prader-Willi (SPW) est une maladie génétique complexe du développement qui résulte de l'absence d'expression de gènes sur le chromosome15q11-q13 paternel. Les patients SPW présentent des taux de GH diminués et des taux de ghréline élevés. Ils sont traités précocement par GH. La région du chromosome 15q11-q13 responsable du SPW est soumise au phénomène d'empreinte génétique, des études récentes la limitent à une région minimale incluant un cluster de small nucleolar RNA (snoARN): le SNORD116. Nos résultats montrent une sensibilité accrue à l'IGF1 et à l'insuline dans les fibroblastes de patients SPW. Ces cellules montrent également un taux augmenté de la prolifération et une diminution de la sénescence. Des études par microarrays, RT-qPCR, ainsi que du sécrétome montrent que l'expression de l'IGFBP7, un important facteur anti-prolifératif, a été considérablement abaissée chez ces patients. IGFBP7 est connu pour interagir avec les récepteurs de l'IGF1 et de l'insuline en modulant négativement leur action. Ces résultats étaient identiques chez la patiente SD. Notre hypothèse a été que l'augmentation de la prolifération et de la sensibilité aux facteurs de croissance est due à l'absence de l'expression du SNORD116. Nous avons démontré que le défaut du SNORD116 entraîne des taux de prolifération élevés et une diminution de la sénescence chez les patients SPW, avec une diminution de la sécrétion de l'IGFBP7. Les taux d'IGFBP7 in vitro décroissent sous l'effet de l'IGF1. De plus nous avons constaté que l'augmentation des taux d'IGF1 était corrélée significativement avec la diminution des taux de l'IGFBP7 chez des enfants SPW traités par GH pendant un an. Ces études soulignent fortement l'importance du SNORD116 pour contrôler la production de l'IGFBP7 en présence d'IGF1 et de facteurs de croissance et donc la sensibilité au traitement à l'hormone de croissance
Prader-willi syndrome (PWS) is a complex genetic disease of neurodevelopment that arises from lack of expression of paternally imprinted genes on chromosome 15q11-q13. GH levels are low in PWS, and GH treatment is recommended. The current management of PWS patients includes early treatment by growth hormone (GH). We demonstrated that GH treatment of PWS patients is associated with elevated IGF1 levels. Human chromosome 15q11-q13 contains an imprinting control region, which when deleted is sufficient to cause PWS. In addition, human genetic studies have defined a minimal PWS gene locus including a cluster of paternally expressed small nucleolar RNA (snoRNA), within the SNORD116. This makes PWS the first human disease found to be caused by loss of non-coding RNA. Our results showed increased sensitivity to IGF1 and Insulin in PWS cells. These cells demonstrate also increased proliferation rate and decreased senescence. From multi-array and RT-qPCR analysis, expression of IGFBP7, an important antiproliferative factor, was dramatically decreased in those patients. IGFBP7 is known to interact with IGF1 and Insulin receptors to decrease their action. We demonstrated that the lack of expression of SNORD116 in this patient results in increased response to IGF1 and Insulin and highly decreased secretion of IGFBP7. Therefore lack of SNORD116 results in high proliferation rate and decreased senescence in PWS, with decreased IGFBP7 secretion. Finally, we found that the increase of IGF1 level was significantly correlated with the decrease of IGFBP7 level in the serum of PWS children treated one year with GH. These data suggest that the lack of SNORD116 expression results in increased responsiveness to growth factors due to a low level of IGFBP7 in cells of PWS patients. They highlight a new phenotype of PWS, modified IGFBP7 levels, which, given the properties of IGFBP7 as a strong regulator of IGF1 effect, has potential consequences on the management of PWS patients treated by GH

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38

Meyer, Joseph Patrick. "The expression and correlations of repressors, intermediaries, and end-products of the IGF1 and insulin signaling pathways within the hepatic and reproductive tissues of holstein cattle h [electronic resource] /." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6085.

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Thesis (Ph. D.)--University of Missouri-Columbia, 2008.
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on August 4, 2009) Vita. Includes bibliographical references.

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Tranesh, Ghassan AB Ahmed MD. "Cross-Talk between IGF/IGFR and Psoriasin (S100A7) Enhancing Growth and Metastasis of Breast Cancer." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1322075360.

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40

Demarquay, Danièle. "Effet de l'hormone de croissance sur la prolifération et la différenciation de chondrocytes de lapin "in vitro" et sur la production d'insulin-like growth factor I(IGF1) par ces cellules." Paris 11, 1992. http://www.theses.fr/1992PA11T017.

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41

Müller, Eva [Verfasser], Wieland [Akademischer Betreuer] Kiess, Jürgen [Akademischer Betreuer] Klammt, Roland [Gutachter] Pfäffle, and Jürgen [Gutachter] Kratzsch. "Klinische und funktionelle Charakterisierung einer stark wachstumsretardierten Patientin mit einer zusammengesetzten heterozygoten Pericentrinmutation und einer heterozygoten IGF1-Rezeptor Mutation. / Eva Müller ; Gutachter: Roland Pfäffle, Jürgen Kratzsch ; Wieland Kiess, Jürgen Klammt." Leipzig : Universitätsbibliothek Leipzig, 2014. http://d-nb.info/1238599869/34.

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42

Benyoucef, Samira. "IR/IGFR hybrids : tools for studying insulin and IGF-1 binding and action." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613706.

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43

Siwanowicz, Igor. "Structural basis for the regulation of insulin-like growth factors (IGFs) by IGF binding proteins (IGFBPs)." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=978174364.

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44

Homberg, Sarah [Verfasser], Heiko [Akademischer Betreuer] Lickert, Heiko [Gutachter] Lickert, and Karl [Gutachter] Kramer. "Characterization of Igfr-L1 and Igfr-L2 as two novel regulators of the Ins/Igf system / Sarah Homberg ; Gutachter: Heiko Lickert, Karl Kramer ; Betreuer: Heiko Lickert." München : Universitätsbibliothek der TU München, 2020. http://d-nb.info/1240383940/34.

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45

Delcroix, Vanessa. "Rôle de Klotho dans la chimiosensibilisation des liposarcomes dédifférenciés : étude des voies de signalisation impliquées." Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0837/document.

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La protéine Klotho (KL) possède des propriétés anti-vieillissement et anti-cancer. Les données cliniques montrent que l’expression de KL est associée à une meilleure survie des patients atteints de liposarcome. De plus, elle est réduite par rapport au tissu sain dans les liposarcomes dédifférenciés (DDLPS), un type de tumeur maligne rare mais de mauvais pronostic. Nos résultats montrent que KL sensibilise les DDLPS aux chimiothérapies (gemcitabine, navitoclax). L’abondance de KL dans les tumeurs pourrait donc servir de biomarqueur pour prédire l’efficacité des chimiothérapies et mettre en place une médecine plus personnalisée. De plus, des médicaments utilisés pour d’autres pathologies et connus pour stimuler l’expression de KL (Cozaar) pourraient être testés en association avec la chimiothérapie. Enfin, inspirés par le mode d’action de KL, nous avons testé la combinaison de la gemcitabine avec le navitoclax, qui s’est révélée très efficace sur les DDLPS
Klotho (KL) is both an anti-ageing and anti-cancer protein. Analysis of clinical data highlights that high expression of KL is associated with a better overall survival of liposarcoma patients. Moreover, its expression in downregulated in dedifferentiated liposarcomas (DDLPS), a rare type of tumor associated with a poor prognosis due to high chemoresistance. Our results show that KL sensitizes DDLPS cells to chemotherapeutic agents (gemcitabine, navitoclax). So, abundance of KL in tumoral tissues could serve as a biomarker for predicting gemcitabine efficacy and so, could help for establishing personalized therapy. Moreover, drugs increasing KL expression could be tested in combination with chemotherapy. Based on KL mechanism of action, we also highlight that the combination between gemcitabine and navitoclax is very effective for killing DDLPS cells

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46

Bassalert, Cécilia. "Influence des voies de signalisation IGF et MAPK sur la spécification des lignages de l'embryon de souris préimplantatoire." Thesis, Université Clermont Auvergne‎ (2017-2020), 2018. http://www.theses.fr/2018CLFAC029.

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Au cours de la préimplantation, l'embryon de souris produit deux lignages cellulaires, le trophectoderme (TE), et la masse cellulaire interne (MCI) qui elle-même se différencie en épiblaste (Epi) et en endoderme primitif (EPr), caractérisés respectivement par l'expression exclusive de Nanog et de Gata6. La voie FGF/MAPK joue un rôle critique dans l’acquisition de l’identité EPr. J’ai examiné l’expression de pERK, DUSP4 et ETV5 qui permettent de visualiser l'activité des MAPK. Ces analyses ont été effectuées en activant ou inhibant la voie FGF/MAPK, ainsi que dans des embryons mutants pour Nanog et/ou Gata6. Ceci a permis d’observer l’activation de la voie FGF/MAPK dès E3,25. Un autre volet de mon travail a été d'analyser la voie de l’IGF dans les embryons préimplantatoires afin de comprendre l’influence de cette voie dans les différents lignages. J’ai montré que le récepteur activé pIGF1R est exprimé de manière différentielle dans le TE, l’EPr et l’Epi au cours du développement. Une supplémentation d’IGF1 induit une augmentation du nombre de cellules en deux phases, d'abord de l’Epi puis de l’EPr. A l’inverse, une perte de fonction d’IGF1R induit une diminution du nombre de cellules entre E3,75 et E4,25
During preimplantation, mouse embryo produces two cellular lineages, the trophectoderm (TE), and the inner cell mass (ICM), which differentiates in epiblast (Epi) and primitive endoderm (PrE), characterized respectively by the complementary expression of Nanog and Gata6. FGF/MAPK pathway plays a critical role in the acquisition of a PrE identity. I examined the expression of the markers of MAPK activity pERK, DUSP4 and ETV5. The analyze was performed with activation or inhibition of FGF/MAPK pathway and in mutant embryos for Nanog or Gata6. This showed that FGF/MAPK pathway is activated as soon as E3,25. I have also analyzed the IGF pathway in preimplantation embryos in order to understand the role of this pathway in embryonic lineages. I showed that active receptor pIGF1R is differentially expressed in TE, PrE and Epi during embryonic development. Supplementation with IGF1 induces an increase in cell number in two phases, first in Epi then in PrE. Conversely, loss of function of IGF1R induces a decrease in cell number between E3,75 and E4,25

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47

Kricker, Jennifer Ann. "Structural investigations into the relationships of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) with vitronectin (VN)." Thesis, Queensland University of Technology, 2005. https://eprints.qut.edu.au/16063/1/Jennifer_Kricker_Thesis.pdf.

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Previous studies demonstrated that IGF-II binds directly to vitronectin (VN) while IGF-I binds poorly. However, binding of VN to integrins has been demonstrated to be essential for a range of IGF-I-stimulated biological effects including IGF binding protein-5 (IGFBP-5) production, IGF type-1 receptor autophosphorylation and cell migration. Thus, this study examined the hypothesis that a link between IGF-I and VN must occur and may be mediated through IGFBPs. Studies using competitive binding assays with VN and [125I]-labelled IGFs in the absence and presence of IGFBPs revealed IGFBP-4, IGFBP-5 and non-glycoyslated IGFBP-3 significantly enhance binding of IGF-I to VN, while IGFBP-2 and glycosylated IGFBP-3 had a smaller effect. Furthermore, binding studies with analogues indicate that glycosylation status of IGFBP-3 and the heparin-binding domains of IGFBP-3 and IGFBP-5 are important in this interaction. The functional significance of IGFs binding to VN on cell migration in MCF-7 breast carcinoma cells was examined and cell migration was found to be enhanced when VN was pre-bound to IGF-I in the presence of IGFBP-3, -4 and -5. The effect required IGF:IGFBP:VN complex formation; this was demonstrated by use of a non-IGFBP-binding analogue, des(1- 3)IGF-I. Additionally, higher doses of IGFs in the presence of VN also could stimulate cell migration. Together, these data indicated the importance of IGFBPs in modulating IGF-I binding to VN and that this binding has functional consequences in cells. Future directions for this work include investigations into the mechanisms underlying formation of the trimeric complex and the associated signalling pathways involved.

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48

Kricker, Jennifer Ann. "Structural investigations into the relationships of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) with vitronectin (VN)." Queensland University of Technology, 2005. http://eprints.qut.edu.au/16063/.

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Abstract:

Previous studies demonstrated that IGF-II binds directly to vitronectin (VN) while IGF-I binds poorly. However, binding of VN to integrins has been demonstrated to be essential for a range of IGF-I-stimulated biological effects including IGF binding protein-5 (IGFBP-5) production, IGF type-1 receptor autophosphorylation and cell migration. Thus, this study examined the hypothesis that a link between IGF-I and VN must occur and may be mediated through IGFBPs. Studies using competitive binding assays with VN and [125I]-labelled IGFs in the absence and presence of IGFBPs revealed IGFBP-4, IGFBP-5 and non-glycoyslated IGFBP-3 significantly enhance binding of IGF-I to VN, while IGFBP-2 and glycosylated IGFBP-3 had a smaller effect. Furthermore, binding studies with analogues indicate that glycosylation status of IGFBP-3 and the heparin-binding domains of IGFBP-3 and IGFBP-5 are important in this interaction. The functional significance of IGFs binding to VN on cell migration in MCF-7 breast carcinoma cells was examined and cell migration was found to be enhanced when VN was pre-bound to IGF-I in the presence of IGFBP-3, -4 and -5. The effect required IGF:IGFBP:VN complex formation; this was demonstrated by use of a non-IGFBP-binding analogue, des(1- 3)IGF-I. Additionally, higher doses of IGFs in the presence of VN also could stimulate cell migration. Together, these data indicated the importance of IGFBPs in modulating IGF-I binding to VN and that this binding has functional consequences in cells. Future directions for this work include investigations into the mechanisms underlying formation of the trimeric complex and the associated signalling pathways involved.

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49

Leal, Andréa de Castro. "Caracterização da insensibilidade ao fator de crescimento insulina-símile tipo 1 em pacientes com defeitos no receptor tipo 1 de IGFs (IGF-1R)." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-30102012-115048/.

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Introdução: Crianças nascidas pequenas para a idade gestacional (PIG) apresentam maior risco de permanecerem com baixa estatura na vida adulta. Os fatores de crescimento insulino-símile tipo 1 e 2 (IGF-1 e IGF-2) são os principais fatores endócrinos determinantes do crescimento fetal. A maioria das ações conhecidas destes hormônios é mediada via um receptor tirosina quinase, conhecido como IGF-1R. As mutações inativadoras e deleções do gene do IGF1R em heterozigose vêm sendo relatadas de forma crescente nos últimos 9 anos em pacientes com história de déficit de crescimento pré e pós-natal. Postula-se que pelo menos 2 a 3% das crianças nascidas PIG poderiam apresentar defeitos no IGF1R. O quadro clínico destes pacientes apresenta grande variabilidade quanto à gravidade do retardo de crescimento pré- e pós-natal e aos parâmetros hormonais. Objetivo: Caracterizar in vitro a resistência ao IGF-1 de pacientes com defeitos no IGF1R, identificados em nosso ambulatório. Material e métodos: Desenvolvemos cultura de fibroblastos de 2 controles (C1 e C2) e de 4 pacientes nascidos PIG (SGA1, SGA2, SGA3 e SGA4) com suspeita de insensibilidade ao IGF-1 por ausência de recuperação do crescimento na vida pós natal. Destes pacientes, um paciente (SGA1) era portador de mutação missense em heterozigose no gene IGF1R (p.Arg511Trp) e os demais apresentavam baixa expressão dos IGF1R em leucócitos periféricos quando avaliados por PCR em tempo real. Um destes pacientes (SGA2) apresentava também a variante alélica p.Gly6Arg do IGF1R em heterozigose, alteração esta encontrada também em controles e familiares sem déficit de crescimento. As ações do IGF-1 foram determinadas por ensaios de proliferação, análise da expressão do IGF-1R e estudos de fosforilação de proteínas da via de sinalização do IGF-1 em fibroblastos (via PI3K). Resultados: As linhagens SGA1, SGA2, SGA3 e SGA4 proliferaram respectivamente 55%, 66%, 64% e 28% a menos sob estímulo de IGF-1 em relação ás linhagens controles. No estudo da expressão do RNAm do IGF1R por PCR em tempo real, foi observada redução na expressão do IGF1R nas linhagens SGA2, SGA3 e SGA4 em relação aos controles, assim como o conteúdo total da proteína IGF-1R. Por outro lado, a linhagem SGA1 mostrou expressão aumentada do IGF1R e no conteúdo da proteína em relação aos controles. Em relação á ativação da via PI3K, todas as linhagens dos pacientes apresentaram menor fosforilação de AKT após estímulo com IGF-1, quando comparadas com as linhagens controles. Conclusão: Demonstramos a presença de insensibilidade parcial ao IGF-1 nas linhagens estudadas. A baixa expressão do IGF1R observada em leucócitos periféricos nas linhagens SGA2, SGA3 e SGA4 foi confirmada em fibroblastos tanto em nível de RNAm quanto da sua proteína. Nestas linhagens a insensibilidade ao IGF-1 é secundária a diminuição da expressão deste receptor. Em contraste a na linhagem com a mutação p.Arg511Trp (SGA1) observou-se expressão normal do IGF-1R na superfície celular. Pacientes com alterações no gene IGF1R não apresentam um fenótipo característico que os diferencie de outras crianças nascidas PIG sem alterações neste gene, mostrando a importância dos estudos moleculares neste grupo de pacientes
Small for gestational age (SGA) children are at a greater risk of having a short stature in adulthood. The type 1 and 2 insulin-like growth factors (IGF-1 and IGF-2) are the main endocrine factors determining fetal growth, and most of the known actions of these hormones are mediated via a receptor tyrosine kinase, IGF-1R. Inactivating mutations and deletions of the IGF1R gene in heterozygosis have been reported with increasing frequency in the last 9 years in patients with a history of a failure to thrive pre- and postnatally. It is postulated that at least 2-3% of the children born SGA could be defective for the IGF1R. The clinical presentation of these patients is highly variable with regard to the severity of growth retardation and pre- and post-natal hormonal parameters. Objectives: The goal of this study was to identify the in vitro insensitivity to IGF-1 in patients with defects in IGF1R. Methods: We developed fibroblast cultures from two controls (C1 and C2) and 4 patients born SGA (SGA1, SGA2, SGA3 and SGA4) with a suspected insensitivity to IGF-1 by the absence of catch-up growth during their postnatal life. Of these patients, one (SGA1) carried a heterozygous missense mutation in the IGF1R gene (p.Arg511Trp), and the others exhibited low expression levels of IGF1R in their peripheral leukocytes, as evaluated using real-time PCR. One of these patients (SGA2) was also heterozygous for the allelic variant p.Gly6Arg of IGF1R, an alteration also found in the controls and family members not displaying growth restriction. The actions of IGF-1 were determined using proliferation assays, an analysis of the expression of IGF- 1R and phosphorylation studies of proteins of the IGF-1 signaling pathway in fibroblasts (via PI3K).Results: The SGA1, SGA2, SGA3 and SGA4 fibroblasts proliferated 55%, 66%, 64% and 28%, respectively, less under the stimulation of IGF-1 compared to the control lines. Using real-time PCR, the IGF1R mRNA expression showed reduced levels of IGF1R in the SGA2, SGA3 and SGA4 cells compared to the controls, and the total IGF-1R protein was also decreased in these cells. Moreover, the SGA1 cells showed increased expression levels of IGF1R mRNA and protein compared to the controls. In relation to the activation of PI3K, all of the cells showed decreased phosphorylation of AKT after the stimulation with IGF-1 compared to the control cells. Conclusion: We demonstrated the presence of a partial insensitivity to IGF-1 in the studied samples. The low expression of IGF1R observed in the peripheral leukocytes in the SGA2, SGA3 and SGA4 fibroblasts was confirmed at both the mRNA and protein levels, and the Andréa de Castro Leal Doutorado insensitivity of the cells to IGF-1 is secondary to the decreased expression of the receptor. In contrast, the cells with the mutation p.Arg511Trp (SGA1) displayed normal IGF-1R expression on the cell surface. The patients with alterations in the IGF1R gene do not exhibit a characteristic phenotype that differentiates them from other children born SGA and with no changes in this gene, thus showing the importance of molecular studies for this group of patients

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Giabicani, Eloïse. "Croissance et système des IGFs (insulin-like growth factors) : l’apport physiopathologique des maladies soumises à empreinte parentale New clinical and molecular insights into Silver–Russell syndrome Roles of Type 1 Insulin-Like Growth Factor (IGF) Receptor and IGF-II in Growth Regulation: Evidence From a Patient Carrying Both an 11p Paternal Duplication and 15q Deletion Diagnosis and Management of Postnatal Fetal Growth Restriction Chromosome 14q32.2 imprinted region disruption as an alternative molecular diagnosis of Silver-Russell Syndrome." Thesis, Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2019SORUS304.pdf.

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La croissance fœtale est sous la dépendance de nombreux facteurs environnementaux, génétiques et hormonaux dont les interactions vont en conditionner le bon déroulement. Le système des insulin-like growth factors (IGFs) joue un rôle prépondérant, à l’interface de ces différents facteurs, pour assurer une bonne croissance fœtale. Dans ce travail, nous nous sommes intéressés aux différents acteurs du système des IGFs dans des pathologies de la croissance fœtale. Dans une approche clinique et expérimentale, nous avons décrit les conséquences fonctionnelles d’anomalies génétiques ou épigénétiques intéressant IGF-I, IGF-II et leur récepteur commun IGF1R. Ainsi, nous avons mis au point un test fonctionnel permettant d’apprécier l’activité in vitro d’IGF1R chez les patients présentant une restriction de croissance fœtale et postnatale. Nous avons également documenté la biodisponibilité d’IGF-I chez des patients présentant un syndrome de Silver-Russell, qui est une pathologie liée à l’empreinte parentale responsable d’une restriction de croissance à début ante-natal. Enfin, nous avons caractérisé le chevauchement clinique et moléculaire entre les patients présentant un SRS ou un syndrome de Temple (autre pathologie liée à l’empreinte parentale), confirmant le rôle prépondérant du défaut d’expression d’IGF2 dans ces deux syndromes. Ces résultats confirment un fonctionnement des gènes soumis à empreinte en réseau et le rôle majeur du système des IGFs dans la croissance fœtale, particulièrement altérée en cas de pathologie intéressant ces gènes soumis à empreinte parentale
Fetal growth is dependant of environemental, genetic and hormonal factors which interact to ensure a proper development. Insulin-like growth factors (IGF) system plays a key role in fetal growth by interactions with these differents systems. In this work, we studied the roles of the IGF system in fetal growth restriction diseases. We used both clinical and experimental approaches to enhance knowledge on functional consequences of genetic ou epigenetic defects of IGF system actors. We set-up a functional test to assess IGF1R activity in vitro in patients with restricted fetal and postnatal growth. We also documented the IGF-I bioavailability in patients with Silver-Russell syndrome, which is an imprinting disorder responsible for fetal and postnatal growth restriction. We characterized the clinical and molecular overlap of Silver-Russell and Temple syndrome (another imprinting disease affecting growth and metabolism) and confirmed the central role of IGF2 in the physiopathology of these disorders. These results confirmed the integration of imprinted genes in a large co-regulation network and the major role of IGF system actors in fetal growth which is usually impaired when these imprinted genes are affected

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Dissertations / Theses on the topic 'IGF1'

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