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Ayari, Sami. "Implication des récepteurs nucléaires HNF-4α et HNF-4γ dans la fonction entéroendocrine et la susceptibilité à l'obésité et au diabète de type II". Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066380.
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L’obésité et le diabète de type 2 (DT2) sont des pathologies métaboliques associées à des perturbations de l’homéostasie glucidique et énergétique. Les enterohormones sont des acteurs importants de la regulation des mécanismes perturbés lors de ces pathologies. Parmi ces enterohormones, le GLP-1, sécrété par les cellules entéroendocrines de type L suite à un repas, permet d’amplifier la sécrétion d’insuline par les cellules β-pancréatiques et de diminuer la prise alimentaire. L’objectif de ma thèse a été de caractériser le rôle du récepteur nucléaire HNF-4γ dans l’homéostasie énergétique et la fonction endocrine de l’intestin.A l’aide d’un modèle murin d’invalidation totale et constitutive du facteur de transcription HNF-4γ, notre équipe a mis en évidence que l’absence de HNF-4γ induit une amélioration de la tolérance au glucose grâce à une augmentation du nombre de cellules L et de la quantité plasmatique de GLP-1 en réponse au glucose. L’ensemble de ces données démontre pour la première fois un rôle de HNF-4γ dans l’homéostasie glucidique via une modulation du lignage enteroendocrine spécifique du GLP-1 et suggère que son absence pourrait protéger les souris de l’établissement d’un DT2.Par ailleurs, la perte d’expression de HNF-4γ confère une protection vis-à-vis de la prise de poids et de l’intolérance au glucose normalement induites par six semaines d’un régime riche en lipides et en fructose grâce une perte énergétique accrue dans les fécès essentiellement due à une malabsorption des acides gras.En conclusion, cette étude met en exergue le rôle du récepteur nucléaire intestinal HNF-4γ dans la fonction enteroendocrine et la susceptibilité à l’obésité et au DT2<br>Obesity and type 2 diabetes (T2D) are metabolic pathologies associated with glucose and energy homeostasis perturbations. Enterohormones are important players in the regulation of the mechanisms disturbed during these pathologies. Among these enterohormones, GLP-1, secreted by enteroendocrine L cells in response to a meal, potentiates insulin secretion by pancreatic β cells and inhibits food intake. The aim of my thesis was to characterize the role of the nuclear receptor HNF-4γ in the energy homeostasis and the endocrine function of the intestine.By using a total and constitutive HNF-4γ knock-out mouse model, our team has highlighted that the loss of hnf-4γ induces an improved glucose tolerance. This effect is due to an increased GLP-1 cell number and GLP-1 plasma levels in response to glucose. All together these data demonstrate for the first time a role of HNF-4γ in glucose homeostasis through a modulation of the enteroendocrine lineage specific for GLP-1 and suggest that its absence could protect mice from the T2D establishment.The loss of HNF-4γ protects mice from body weight gain and glucose intolerance normally induced by six weeks of a high-fat/high-fructose diet demonstrating its involvement in obesity and T2D. HNF-4γ -/- mice are protected from obesity by a greater energy loss in faeces mainly due to lipid malabsorption. These results demonstrate that HNF-4γ is necessary for the intestinal fatty acids uptake.In conclusion, this study highlights the role of the intestinal nuclear receptor HNF-4γ in enteroendocrine function and susceptibility to obesity and T2D
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Gu, Ning. "Effects of mutant HNF-1α and HNF-1β identified in MODY3 and MODY5 on the sucrase-isomaltase and dipeptidylpeptidase-4 gene expressions". Kyoto University, 2007. http://hdl.handle.net/2433/136420.
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Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(人間・環境学)<br>甲第13147号<br>人博第354号<br>新制||人||88(附属図書館)<br>18||D||155(吉田南総合図書館)<br>UT51-2007-H420<br>京都大学大学院人間・環境学研究科共生人間学<br>(主査)教授 石原 昭彦, 教授 津田 謹輔, 助教授 林 達也<br>学位規則第4条第1項該当
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Wikner, Martin. "Malmölärares syn på sexuella normavvikelser i årskurs 4-6." Thesis, Malmö högskola, Lärarutbildningen (LUT), 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:mau:diva-27730.
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Arbetet försöker belysa och förstå hur några lärare i årskurs 4-6 i Malmö ser på frågor om homosexualitet, bisexualitet och transpersoner (HBT) ur ett queerperspektiv. Frågeställningarna handlar om hur lärarna anser att HBT-frågor hanteras bäst i mötet med eleverna i och utanför klassrummet, vilken syn de har på kollegor och föräldrar som är HBT samt grundsynen i HBT-frågor. Undersökningen genomfördes med enkäter som syftade till att ge kvalitativa svar och skickades ut till olika skolor i Malmö kommuns stadsdelar. Resultatet visar på att den allmänna synen bland lärarna är att heterosexualitet är viktigare att undervisa i än homo- och bisexualitet samt transsexualitet. Synen på HBT-personer är accepterande, men hamnar lätt i skymundan bakom heterosexuella normer.
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Dimitrova, Tatyana Stefanova [Verfasser]. "Inhibition of HIF prolyl 4-hydroxylases protect endothelial cells from apoptosis / by Tatyana Stefanova Dimitrova." Giessen : VVB Laufersweiler, 2010. http://d-nb.info/1009522264/34.
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Määttä, J. (Jenni). "Effects of the hypoxia response on metabolism in atherosclerosis and pregnancy." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526222394.
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Abstract Oxygen is vital for human survival. To ensure its sufficient supply, the body has an intricate system, which involves the circulatory, respiratory and neuroendocrine systems. When oxygen is lacking, a state of hypoxia occurs, and adaptive changes in gene expression increase oxygen delivery to promote survival. The key regulator of the transcriptional hypoxia response is hypoxia-inducible factor (HIF) which targets over 1000 genes. The HIF prolyl 4-hydroxylases (HIF-P4Hs) govern the stability of HIF in an oxygen-dependent fashion. In our studies we investigated whether activation of the hypoxia response through inhibition of either of two distinct HIF-P4Hs, HIF-P4H-2 or P4H-TM would reduce atherosclerosis in mice. We found that inhibition of HIF-P4H-2 led to reductions in numbers of atherosclerotic plaques, and levels of serum cholesterol and inflammation in white adipose tissue and aortic plaques. In addition, HIF-P4H-2 deficient mice had elevated levels of modified LDL-targeting, atheroprotective circulating autoantibodies. The P4H-TM knockout mice also had reduced numbers of atherosclerotic plaques and increased levels of atheroprotective autoantibodies in their sera, but in contrast to the HIF-P4H-2 deficient mice, they also showed a reduction in serum triglyceride levels. To determine how hypoxia alters maternal glucose and lipid metabolism in pregnancy, we studied pregnant mice that were predisposed to a hypoxic condition (15% ambient O2). We found that they had enhanced glucose metabolism due to reduced insulin resistance and an increased flux of glucose to maternal tissues. The hypoxic dams also failed to gain weight and store adipose tissue in the anabolic phase to the same extent as normoxic control dams. These results implicate HIF-P4H inhibition as a novel therapeutic mechanism for atherosclerosis, and suggest that the small molecule HIF-P4H inhibitors currently in clinical trials for renal anemia may have further possible therapeutic applications. In addition, greater understanding of the changes in maternal metabolism that underly reduced fetal growth in hypoxic conditions, and the development of targeted interventions may allow the preservation of fetal growth in cases of maternal hypoxia<br>Tiivistelmä Happi on ihmiselle elintärkeää. Tämän vuoksi meille on kehittynyt pitkälle jalostunut verenkierto-, hengitys- ja neuroendokriininen järjestelmä sekä sellaisten geenien ilmentymisen muutoksia, jotka joko lisäävät hapen kuljetusta tai auttavat selviytymään hypoksisissa oloissa, jotta taataan riittävä hapen saanti. Hapen puutteessa hypoksiavaste, jonka tärkein säätelijä on hypoksiassa indusoituva transkriptiotekijä (HIF), aktivoituu. HIF:lla on yli 1000 kohdegeeniä joiden kautta sen vaikutukset välittyvät. HIF-prolyyli-4-hydroksylaasit (HIF-P4H:t) säätelevät HIF:n stabiilisuutta hapesta riippuvaisesti. Tutkimuksessamme selvitimme, vähentääkö hypoksiavasteen aktivointi HIF-P4H-2:n tai P4H-TM:n inhibition kautta ateroskleroosia hiirillä. Tuloksena oli, että HIF-P4H-2:n inhibitio vähensi ateroskleroottisia plakkeja, seerumin kolesterolia ja inflammaatiota valkoisessa rasvakudoksessa sekä plakeissa. Lisäksi hiirillä, joilta puuttui HIF-P4H-2, oli lisääntynyt määrä ateroskleroosilta suojaavia muokattua LDL:ää sitovia autovasta-aineita seerumissa. P4H-TM-poistogeenisillä hiirillä todettiin vastaavasti vähemmän ateroskleroottisia plakkeja ja lisääntynyt määrä ateroskleroosilta suojaavia autovasta-aineita seerumissa. Poiketen HIF-P4H-2-puutteisista hiiristä, niillä oli matalammat seerumin triglyseridi-tasot. Tutkimme raskaina olevia hiiriä, jotka altistimme hypoksisille olosuhteille (15% O2), jotta pystyisimme määrittämään, kuinka hypoksia vaikuttaa äidin sokeri- ja rasva-aineenvaihduntaan. Hypoksiassa raskaana olevilla hiirillä todettiin tehostunut sokeriaineenvaihdunta, joka oli seurausta alentuneesta insuliiniresistenssistä sekä lisääntyneestä sokerin sisäänotosta äidin kudoksiin. Hypoksiassa eivät raskaana olevien hiirten paino eivätkä rasvavarastot lisääntyneet samassa suhteessa normoksiassa raskaana olevien hiirten kanssa. Nämä tulokset tarjoavat uusia mahdollisuuksia HIF-P4H-inhibition käyttämiseen terapeuttisena vaihtoehtona ateroskleroosin hoidossa ja ehkäisemisessä. Kliinisissä kokeissa munuaisperäisen anemian hoidossa olevat HIF-P4H-estäjät voisivat näin ollen saada lisää indikaatioita. Lisäksi korkean ilmanalan aiheuttaman pienipainoisuuden takana olevien aineenvaihdunnan muutoksien ymmärtäminen voi mahdollistaa sikiön kasvun turvaamisen spesifein interventioin
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Coêlho, Harnôldo Colares. "Presença dos vírus HBV e HCV e seus fatores de riscos nos presidiários masculinos da penitenciária de Ribeirão Preto." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/17/17138/tde-15052008-140503/.
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Infecções pelos vírus da hepatite B (HBV) e vírus da hepatite C (HCV) na população prisional apresentam prevalências bastante elevadas, alcançando taxas, algumas vezes, de mais de 40%. Contribuem para isso diversos comportamentos de risco, adotados já antes do encarceramento ou desenvolvidos durante o período de reclusão. Entre eles, destacam-se o uso de drogas ilícitas intravenosas com compartilhamento de agulhas, tatuagens e atividade sexual desprotegida. Esta pesquisa objetivou estimar a prevalência dos marcadores do HBV e HCV com seus respectivos fatores de risco para estas exposições na população masculina carcerária da Penitenciária de Ribeirão Preto - SP, no período de maio a agosto de 2003. Do total de 1030 presidiários, foram sorteados 333 participantes por amostragem casual simples, os quais foram submetidos à aplicação de um questionário padronizado e tiveram coletada uma amostra de sangue. Para diagnóstico do HBV e HCV foi utilizado o ensaio imunoenzimático para detecção do HBsAG, anti-HBc total, anti-HBs e anti-HCV. A confirmação deste foi feita através de reação de polimerase em cadeia (HCV RNA). As prevalências encontradas para HBV e HCV nos presidiários foram de 19,5%% (IC 95% : 15,2 - 23,8) e 8,7% (IC 95% : 5,7 - 11,7), respectivamente . Todas as variáveis que apresentaram \"p\" abaixo de 0,25, através de análise univariada, foram submetidas a um modelo multivariado de regressão logística. Nesta análise, as variáveis que se mostraram preditoras de forma independente da infecção pelo HBV foram: idade acima de 30 anos e passado de droga injetável. Já para o HCV, as variáveis foram idade acima de 30 anos, história prévia de hepatite, tatuagem, passado de droga injetável e passado de compartilhamento de agulhas.<br>The hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in correctional settings have quite high prevalences, reaching rates of up to 40%. Several risk behaviors, adopted before or during the imprisonment, accounts for that. Among them, the use of intravenous illicit drugs, sharing of needles, tattoos and unprotect sexual activity are the most important. This survey aimed to estimate the prevalence of HBV and HCV serological marker and risk factors for these infections in men inmates at the Penitentiary of Ribeirão Preto, State of São Paulo, Brazil, between May and August 2003. Out of 1030 inmates, a simple random sample of 333 participants was chosen. The participants were interviewed in a standardized questionnaire and provided blood for serological tests. An enzyme-linked immunosorbent assay (ELISA) was used for diagnosis of HBV and HCV infection (HBsAg, anti-HBs, anti-HBc, anti-HCV). Polymerase chain reaction (HCV RNA) was used to confirm HCV infection. The overall prevalence for HBV and HCV markers in inmates was 19,5% (CI 95%: 15,2 - 23,8) and 8,7% (CI 95%: 5,7 - 11,7), respectively. The variables that displayed p<0,25, through univariate analysis, were assessed by a logistic regression multivariate model. At the level of 5%, HBV infection was associated with age > 30 years and previous injecting drug use. For HCV infection, age > 30 years, previous injecting drug use, previous sharing of needles, tattoos and previous hepatitis.
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Hao, Wei. "THE MAP KINASE AND TCF-4 SIGNALING PATHWAYS REGULATE HIF-1A TRANSCRIPTIONAL ACTIVITY IN RESPONSE TO HYPOXIA." Thesis, The University of Arizona, 2009. http://hdl.handle.net/10150/192464.
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Karsikas, S. (Sara). "Hypoxia-inducible factor prolyl 4-hydroxylase-2 in cardiac and skeletal muscle ischemia and metabolism." Doctoral thesis, Oulun yliopisto, 2015. http://urn.fi/urn:isbn:9789526207810.
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Abstract Oxygen is essential for aerobic organisms, as shortage of oxygen (hypoxia) can induce cellular dysfunctions and even cell death, leading to tissue damage and decreased viability of the organism. Oxygen homeostasis is regulated delicately by several mechanisms, the major one being the hypoxia-inducible factor (HIF) pathway that is evolutionarily conserved. HIFα subunits are regulated in an oxygen-dependent manner via three HIF prolyl 4-hydroxylases (HIF-P4Hs). In the presence of oxygen HIF-P4Hs modify HIFα, which leads to its degradation, whereas in hypoxia the HIF-P4H enzymes cannot function and HIFα is stabilized. HIF regulates more than 300 genes that enhance oxygen delivery from the lungs to tissues and reduce oxygen consumption in tissues, such as those for erythropoietin and vascular endothelial growth factor. When a tissue suffers from hypoxia caused by a circulatory restriction, the situation is called ischemia. In this study we used a genetically modified HIF-P4H-2 hypomorph mouse line that expresses 8% of the wild-type Hif-p4h-2 mRNA in the heart and 19% in skeletal muscle, and has HIFα stabilization in both tissues. We showed that chronic HIF-P4H-2 deficiency leads to protection against acute ischemic injury both in the heart and in skeletal muscle. The protection was mainly due to enlarged capillaries and better perfusion in both tissues. Hypoxia is known to decrease body weight. The observation of the HIF-P4H-2 deficient mice being leaner than their wild-type littermates led us to study their body constitution, metabolism and adipose tissue in detail. We discovered that chronic HIF-P4H-2 deficiency protects against obesity and several metabolic dysfunctions including diabetes and metabolic syndrome. These beneficial outcomes were mimicked when a pharmacological pan-HIF-P4H inhibitor was administered to wild-type mice. In these studies we showed that pharmacological HIF-P4H-2 inhibition may provide a novel treatment for diseases such as acute myocardial infarction, peripheral artery disease and metabolic disorders<br>Tiivistelmä Happi on edellytys aerobisen eliön, kuten ihmisen, elämälle; hapen niukkuus (hypoksia) voi johtaa monenlaisiin solun toimintahäiriöihin, jotka voivat edelleen aiheuttaa solun kuoleman, kyseisen kudoksen vaurion, ja lopulta eliön elinkyvyn heikkenemisen. Happitasapainoa säädellään monilla menetelmillä, joista merkittävin on hypoksiassa indusoituvasta tekijästä (HIF) riippuvainen reitti, joka on evoluutiossa säilynyt. HIFα alayksiköitä säätelee hapesta riippuvaisesti kolme HIF prolyyli 4-hydroksylaasia (HIF-P4Ht). Hapen läsnä ollessa HIF-P4H on aktiivinen ja johtaa HIFα:n hajottamiseen, kun taas hypoksiassa HIF-P4H entsyymit eivät voi toimia ja siten HIFα stabiloituu. HIF säätelee yli 300 geeniä, jotka edistävät hapen kuljetusta ja pääsyä keuhkoista kudoksiin sekä vähentävät hapenkulutusta. Näitä geenejä ovat mm. erytropoietiini sekä vaskulaarinen endoteelikasvutekijä. Kudoksen heikentyneestä verenkierrosta johtuvaa hapenpuutetta kutsutaan iskemiaksi. Tässä tutkimuksessa käytimme geneettisesti muunneltua HIF-P4H-2 hypomorfi-hiirikantaa, joka tuottaa Hif-p4h-2 lähetti-RNA:ta sydämessä vain 8 % ja luurankolihaksessa 19 % villityypin määrästä, ja jolla on HIFα stabiloituneena molemmissa kudoksissa. Osoitimme, että krooninen HIF-P4H-2:n puute suojaa sekä sydäntä että luurankolihasta akuutissa iskemiassa. Vaikutus johtui pääasiassa suuremmista kapillaareista ja paremmasta perfuusiosta molemmissa kudoksissa. Aikaisempien tutkimusten perusteella tiedetään, että hypoksia alentaa painoa. Huomio siitä, että HIF-P4H-2 puutteiset hiiret ovat hoikempia kuin villityypin sisaruksensa, johti meidät tutkimaan hiirten kehon koostumusta, aineenvaihduntaa ja rasvakudosta tarkemmin. Tutkimuksissamme selvisi, että krooninen HIF-P4H-2:n puute suojaa lihavuudelta ja monelta aineenvaihdunnan häiriöltä kuten sokeritaudilta ja metaboliselta oireyhtymältä. Nämä edulliset vaikutukset toistuivat, kun annoimme villityypin hiirille pan-HIF-P4H inhibiittoria. Kaiken kaikkiaan, näissä tutkimuksissa osoitimme, että lääkkeellinen HIF-P4H-2:n estäminen voi tarjota uuden keinon sydäninfarktin, luurankolihasiskemian ja aineenvaihdunnan häiriöiden hoitoon
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Ahmed, Raju. "Investigation of the effects of different cryopreservation parameters on the genome of 51/4 hpf zebrafish (Danio rerio) embryos." Thesis, University of Bedfordshire, 2013. http://hdl.handle.net/10547/322165.
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In recent years, numerous studies have linked cryopreservation with increased occurrence of mutations, DNA fragmentation and the event of apoptosis in biological objects. However, the evidence emerged from such studies is somewhat inconclusive. The current study, therefore, aimed to analyse the DNA damage response (DDR) from the cryopreserved cells in order to characterise the nature of the putative DNA damage. The study set out to investigate the effects of different cryopreservation parameters on the genome in terms of double strand breaks (DSBs), single strand breaks (SSBs), and various forms of sequence alteration using 5¼ hour post fertilisation (hpf) zebrafish (Danio rerio) embryos. The experimental conditions under which the investigation was carried out were short term chilling at 0˚C, treatment with two cryoprotective agents (CPA), namely, MeOH and Me2SO, and cooling to -35˚C. Assays for detecting DSB-activated DDR proteins and SSB-activated DDR proteins in 5¼ hpf zebrafish (Danio rerio) were developed and then utilised to investigate the occurrence of DSBs and SSBs in the genome of the embryos treated with the experimental conditions. The study then analysed the expression profiles of a set of genes unique to the base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR) pathways as indicators of the occurrence of various forms of sequence alterations in the genome of the embryos treated with the experimental conditions. It was found that chilling and CPA treatment did not induce DSBs or SSBs but up-regulated the MMR and BER, respectively. CPA treatment also down-regulated the NER and the MMR mechanisms. Cooling, on the contrary, did not induce DSBs but induced SSBs in the genome, which were repaired when the embryos were provided with a recovery time. Cooling also up-regulated the NER and the BER mechanisms in the embryos. The overall finding of the study indicated that the experimental conditions increased the occurrence of various single stranded DNA lesions in the genome of the embryos. The present study provided important insights into how eukaryotic cells respond to different cryopreservation parameters, which will significantly enhance the current knowledge of the effects of cryopreservation on the genome of biological objects.
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GUESNE, HERAUD CATHERINE. "Prevalence de l'antigene hbs chez les femmes enceintes suivies au chu de limoges : etude sur une periode de 4 ans." Limoges, 1988. http://www.theses.fr/1988LIMO0103.
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Hyvärinen, J. (Jaana). "Enzymes involved in hypoxia response:characterization of the in vivo role of HIF-P4H-2 in mouse heart, of a novel P4H in human and zebrafish and of the catalytic properties of FIH." Doctoral thesis, University of Oulu, 2010. http://urn.fi/urn:isbn:9789514261947.
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Abstract Oxygen homeostasis is critical to all animals, as both excess (hyperoxia) and reduced (hypoxia) levels of oxygen can result in pathological changes and ultimately in the loss of cellular and organismal viability. Complex systems have evolved to sense and adapt to changes in cellular oxygen availability, and the hypoxia-inducible factor HIF plays a pivotal role in this elaborate molecular network. In normoxic conditions the α-subunit of HIF becomes hydroxylated by HIF prolyl 4-hydroxylases (HIF-P4Hs 1-3), earmarking HIF-α for proteasomal degradation. Additionally, in the presence of oxygen the hydroxylation of an asparagine residue by the HIF asparaginyl hydroxylase FIH inhibits the transactivation of HIF-target genes by blocking the interaction of HIF-α with a transcriptional coactivator. In addition to being a feature of an organism’s normal life, hypoxia is also characteristic of many common diseases such as severe anemia and myocardial infarction, and it notably decreases these hydroxylation reactions, as HIF-P4Hs and FIH have an absolute requirement for oxygen as a cosubstrate. HIF-α thus escapes degradation and translocates into the nucleus, where it dimerizes with HIF-β and recruits transcriptional coactivators to the hypoxia-response elements of target genes, inducing their transcription and triggering the hypoxia response aimed at restoring cellular oxygen homeostasis. In this study we generated a genetically modified HIF-P4H-2 hypomorphic mouse line that expresses only 8% of the wild-type HIF-P4H-2 mRNA in the heart. We showed that chronic cardiac HIF-P4H-2 deficiency leads to stabilization of HIF-1α and HIF-2α and protects the heart against acute ischemia-reperfusion injury without causing any adverse effects. Furthermore, we identified and cloned a novel human transmembrane prolyl 4-hydroxylase P4H-TM and showed that it regulates HIF-1α protein levels in cellulo and hydroxylates HIF-1α in vitro similarly to the HIF-P4Hs, but may also have other physiological substrates. Using forward genetic tools we showed that lack of P4H-TM during development leads to basement membrane defects and compromised kidney function in zebrafish embryos. Finally, we demonstrated that FIH displays substrate selectivity in terms of hydroxylation and binding of HIF-1α and novel substrates Notch1-3. We showed that FIH has higher affinity for oxygen with Notch1 than with HIF-1α as a substrate, implying that FIH-mediated hydroxylation of Notch can continue in oxygen concentrations where HIF-1α hydroxylation would be markedly reduced<br>Tiivistelmä Happitasapainon ylläpito on edellytys elimistön normaalille toiminnalle, koska sekä liian korkea (hyperoksia) että liian matala (hypoksia) happipitoisuus ovat elimistölle stressitiloja ja johtavat pitkittyessään haitallisiin seurauksiin. Happipitoisuuden muutosten havaitsemiseksi ja niihin reagoimiseksi onkin elimistössä kehittynyt monimutkainen säätelyjärjestelmä, jossa avainasemassa on hypoksia-indusoituva tekijä HIF. Solun happipitoisuuden ollessa normaali yksi kolmesta HIF prolyyli 4-hydroksylaasi-isoentsyymistä (HIF-P4Ht 1-3) katalysoi kahden proliinitähteen hydroksylaation HIF-α-alayksikössä. 4-hydroksiproliini toimii signaalina HIF-α:n nopealle proteasomaaliselle hajotukselle. Lisäksi HIF asparaginyyli hydroksylaasi FIH:n katalysoima HIF-α:n asparagiinitähteen hydroksylaatio estää transaktivaatiovaikutuksen. Koska HIF-P4Ht ja FIH tarvitsevat kosubstraatikseen happea, nämä hydroksylaatioreaktiot vähenevät happipitoisuuden laskiessa, jolloin HIF-α stabiloituu ja siirtyy solun tumaan, jossa se muodostaa kompleksin HIF-β-alayksikön kanssa ja houkuttelee paikalle tarvittavat kofaktorit. HIF-kompleksi tehostaa hypoksiavasteessa tarvittavien geenien luentaa sitoutumalla tumassa niiden promoottoreihin ja pyrkii näin palauttamaan solun happipitoisuuden normaaliksi. Tässä työssä luotiin geneettisesti muunneltu HIF-P4H-2 hypomorfi-hiirilinja, jonka sydämissä tuottuu vain 8 % normaalista HIF-P4H-2 lähetti-RNA:n määrästä. HIF-P4H-2:n puutoksen havaittiin johtavan HIF-1α:n ja HIF-2α:n stabiloitumiseen sydämessä ja suojaavan sydäntä kudosvaurioilta iskemian ja reperfuusion aikana aiheuttamatta haitallisia vaikutuksia. Tässä väitöskirjassa karakterisoitiin aiemmin tuntematon ihmisen transmembraaninen prolyyli 4-hydroksylaasi, P4H-TM. Sen osoitettiin säätelevän HIF-1α:n määrää soluissa ja katalysoivan HIF-1α:n kahden proliinitähteen hydroksylaatiota in vitro-olosuhteissa HIF-P4H-entsyymien tavoin. Seeprakalamallin avulla näytettiin, että P4H-TM:n puutos kalan kehityksen aikana aiheuttaa tyvikalvopoikkeavuuksia ja johtaa vakavaan munuaisen toiminnan häiriintymiseen seeprakalan poikasissa. FIH:n katalysoiman hydroksylaatioreaktion kineettisiä ominaisuuksia verrattiin tässä tutkimuksessa ensimmäistä kertaa aiemmin tunnetun HIF-α substraatin ja uusien Notch substraattien kesken. Tulokset osoittivat, että substraatin sitomisessa ja hydroksylaatiossa on merkittäviä eroja eri substraattien välillä
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Place, Trenton Lane. "A novel role for prolyl-hydroxylase 3 gene silencing in epithelial-to-mesenchymal-like transition." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/1726.
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The ability of cells to sense oxygen is a highly evolved process that facilitates adaptations to the local oxygen environment and is critical to energy homeostasis. In vertebrates, this process is largely controlled by three intracellular prolyl-4-hydroxylases (PHD 1-3). These related enzymes share the ability to hydroxylate the hypoxia-inducible transcription factor (HIF), and therefore control the transcription of genes involved in metabolism and vascular recruitment. However, it is becoming increasingly apparent that proline-4-hydroxylation controls much more than HIF signaling, with PHD3 emerging as the most unique and functionally diverse of the PHD isoforms. In fact, PHD3-mediated hydroxylation has recently been purported to function in such diverse roles as sympathetic neuronal and muscle development, sepsis, glycolytic metabolism, and cell fate. PHD3 expression is also highly distinct from that of the other PHD enzymes, and varies considerably between different cell types and oxygen concentrations. This thesis will specifically examine the role of PHD3 expression in cancer cells, with a focus on the mechanisms of PHD3 gene silencing. In the final chapters, I will examine the consequences of this silencing in cancer, and discuss the discovery of a novel role for PHD3 in epithelial-to-mesenchymal-like transition and cell migration.
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Pisarenko, Irina [Verfasser], та Joachim Kurt [Akademischer Betreuer] Fandrey. "Interaktionsanalyse der Hypoxie-induzierbaren Transkriptionsfaktoren HIF-2α und ARNT unter Berücksichtigung der Einflussnahme durch den HIF-2α-Liganden N-(3-Chloro-5-fluorophenyl)-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine und verschiedener HIF-2α-Mutationen / Irina Pisarenko ; Betreuer: Joachim Kurt Fandrey". Duisburg, 2018. http://d-nb.info/1159879133/34.
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Al, Lawati Aida. "Molecular-genetic analysis of the Hyf gene-cluster encoding the Hydrogenase-4 system of E. coli : role in hydrogen production." Thesis, University of Reading, 2018. http://centaur.reading.ac.uk/80703/.
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In E. coli, four types of hydrogenases are recognized. Hydrogenases 1 (Hyd-1) and 2 (Hyd-2) are responsible for H2 consumption via respiration. Hydrogenase-3 (Hyd-3), which is encoded by the hycABCDEFGHI operon, combines with formate dehydrogenase H (Fdh-H) to form the formate hydrogen lyase (FHL) complex, which is responsible for formate disposal and H2 evolution during anaerobic fermentation under acidic pH. The hyfABCDEFGHIJR-focB operon of E. coli encodes a fourth potential hydrogenase (Hyd- 4) closely related to Hyd-3. The physiological purpose of the Hyf system is unclear although it is speculated to form a second, energy conserving, FHL with Fdh-H. However, current evidence suggests that the hyf operon is not expressed and may thus be cryptic. The aim here is to discover whether the Hyf/Hyd-4 system is indeed capable of hydrogenase activity and can thus be assigned a fourth hydrogenase. Analysis of the NCBI database showed that hyf is conserved in all E. coli/Shigella stains, except for the most basal phylogroup (B2) which is associated with avian- and uro-pathogenic strains; this might suggest a role for Hyf in colonisation of the mammalian intestine. To determine if hyf-encoded FocB acts as a second formate channel, a focA mutant was complemented with focB carried by pBADrha. Rhamnose induction of focB restored sensitivity to hypophosphite (formate analogue) supporting a role for FocB as a second formate channel. Similarly, induction of pBADrha-encoded focA also restored hypophosphite sensitivity. FocA supported H2 production at low pH, but had little impact at high pH. Low levels of FocB could compensate for absence of FocA. Plasmid induced focA restored the levels of formate released in a focA mutant at pH 6.5, to those seen in the wildtype, whereas plasmid induced focB increased such levels more modestly, although both FocA and FocB supported fermentative growth at pH 6.5. Expression of focB appeared toxic at pH 7.5. Thus, the results generally support a role for FocB in formate export and suggest roles in delivery of exogenous formate to FHL-1 indicating a role in formate import also under acidic pH conditions. When a hycE mutant strain was complemented with hyf carried by pBADrha at pH 6.5, H2 production was restored, and this was accompanied by restoration of formate consumption; a similar effect was seen upon plasmid-borne hyc induction. This indicates that hyf specifies an active hydrogen-evolving hydrogenase. Complementation of a ΔfdhF ΔhycE double mutant with both hyf and fdhF, carried by pBADrha and pBADara, respectively, re-enabled H2 production and formate consumption, thus showing that Hyf activity is Fdh-H dependent indicating that Hyf and Fdh-H combine to form a second FHL (FHL-2). FHL-2 activity was formate concentration dependent, with increased H2 production with increased formate provided. Induced-Hyf H2-production activity was enhanced by provision of nickel at up to 0.25 mM (but was inhibited at 0.5 mM nickel) supporting the presence of Ni in the proposed [NiFe] centre of the Hyf-hydrogenase. Molybdenum and selenium were also shown to be required for high Hyf-FdhH (FHL-2) H2-production activity. In conclusion, this thesis provides strong evidence showing that the hyf-focB locus encodes a second formate channel and a fourth hydrogenase (Hyd-4) in E. coli, with the Hyd-4 enzyme acting as an H2 producing and formate dependent enzyme that forms a second FdhF-dependent FHL complex. Further work is required to establish the environmental conditions under which the Hyf system is active, and offers an advantage, in the wildtype.
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Pramanik, Preeti. "Characterization of the FTF/HNF-4 Sites Within the 7Alpha- and the 12Alpha-Hydroxylase Promoters Involved in the Bile Acid-Mediated Transcription of their Regulation." VCU Scholars Compass, 2006. http://scholarscompass.vcu.edu/etd/1064.
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Bile acids regulate their own synthesis through a feedback regulatory mechanism of mainly two enzymes in the classic pathway, the 7α-hydroxylase and the 12α-hydroxylase. In the early 1990's it was shown that the regulatory responses of 7α-hydroxylase are mediated at the transcriptional level and since then many positive and negative transcription factors that mediate regulatory response have been identified. An important finding was that the transcription factors regulating the expression of 7α- and 12α-hydroxylase genes are nuclear receptors.One of the first nuclear receptors identified to play a role in the transcription of the 7α-hydroxylase gene was HNF-4 since then many nuclear receptors have been identified that are involved in regulating the 7α- and 12α-hydroxylase genes. Among them the most important ones are FTF and HNF-4 which has been shown to play crucial roles in the transcription and regulation by bile acids. In this study we demonstrate the importance of FTF and HNF-4 independent of each other in the transcription and bile acid-mediated regulation of the 7α- and 12α-hydroxylase enzymes by creating promoter mutants that would either bind FTF or HNF- 4. Once the binding studies were established we performed tissue culture experiments to confirm the promoter activity and bile acid-mediated regulation with the respective promoter mutant constructs. The data from this study shows that HNF-4 is important for 7α-hydroxylase promoter activity but is not required and importantly we show that HNF-4 is not a required for the bile acid-mediated regulation of the 7α-hydroxylase. We present data which suggests that FTF is absolutely required for the promoter activity and bile acid-mediated regulation of 7α-hydroxylase. With respect to the 12α-hydroxylases how that both FTF and HNF-4 are absolutely required for promoter activity. In this study we present evidence that since the bile acid responsive elements (BARE) are similar within both the 7α- and 12α-hydroxylase promoters one can be exchanged for the other maintaining both activity and bile acid-mediated regulation.
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Myllymäki, M. (Mikko). "Hypoxia-inducible factor prolyl 4-hydroxylase-2 in Tibetan high-altitude adaptation, extramedullary erythropoiesis and skeletal muscle ischemia." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526212210.
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Abstract Adequate oxygen supply is necessary for aerobic cell survival. Cellular oxygen deprivation, also known as hypoxia, leads to various responses that aim to increase cellular oxygen delivery and reduce oxygen consumption. Oxygen homeostasis is mainly regulated by the hypoxia-inducible factor (HIF), which regulates the expression of over 300 genes in response to hypoxia. The stability of HIF is regulated by the HIF prolyl 4-hydroxylases (HIF-P4Hs), enzymes that catalyze the hydroxylation of proline residues in HIFα subunits and target them towards proteasomal degradation. HIF-P4Hs require oxygen as a cosubstrate for the reaction, allowing for hypoxic HIF stabilization and target gene induction at low oxygen concentrations. In this study we investigated the role of HIF-P4H-2 in the regulation of red blood cell production, erythropoiesis. We showed that Tibetans living at high altitude have genetically adapted to their hypoxic environment via mutations in the gene encoding for HIF-P4H-2. The Tibetan HIF-P4H-2 D4E,C127S variant showed enhanced hydroxylation of HIFα at low oxygen concentrations, resulting in reduced HIFα protein stabilization under hypoxia. In other studies we used a genetically modified HIF-P4H-2 hypomorphic mouse line which expresses a reduced amount of wild-type Hif-p4h-2 mRNA in tissues. We showed that these mice develop mild age-dependent erythrocytosis due to splenic extramedullary erythropoiesis, which is independent of serum erythropoietin concentration. In addition, these mice were protected against inflammation-induced anemia, a condition commonly seen in patients with inflammatory diseases. The HIF-P4H-2 hypomorphic mice also had altered basal metabolism in their skeletal muscles, which, together with an increase in mean capillary area, reduced their infarct size after skeletal muscle ischemia-reperfusion injury. These studies suggest that pharmacological HIF-P4H-2 inhibition may provide a novel treatment for EPO-resistant anemias and peripheral artery disease<br>Tiivistelmä Riittävä hapensaanti on välttämätöntä aerobisten solujen selviytymiselle. Solun alentunut hapen määrä, toiselta nimeltään hypoksia, johtaa useisiin vasteisiin joiden tarkoituksena on turvata solun hapensaanti ja vähentää hapenkulutusta. Happitasapainoa säätelee hypoksiassa indusoituva tekijä (HIF), joka aktivoi yli 300 geenin luentaa hypoksisissa oloissa. HIFα:n määrää soluissa säätelevät HIF prolyyli-4-hydroksylaasientsyymit (HIF-P4H:t), jotka hydroksyloivat proliini-aminohappotähteitä HIFα-alayksiköissä ja ohjaavat ne proteasomaaliseen hajotukseen. HIF-P4H:t tarvitsevat reaktiossa happea mahdollistaen HIF:n stabilisaation ja kohdegeenien lisääntyneen luennan matalassa hapen osapaineessa. Tässä tutkimuksessa selvitimme HIF-P4H-2-entsyymin roolia punasolujen muodostuksen eli erytropoieesin säätelyssä. Osoitimme, että korkealla vuoristossa asuvat tiibetiläiset ovat geneettisesti sopeutuneet hypoksiseen elinympäristöönsä johtuen HIF-P4H-2-entsyymiä tuottavan geenin mutaatiosta. Tiibetiläisiltä löytynyt HIF-P4H-2D4E,C127S variantti hydroksyloi tehokkaammin HIFα-alayksiköitä matalassa hapen osapaineessa johtaen vähäisempään HIFα-alayksiköiden stabiloitumiseen hypoksiassa. Muissa tutkimuksissamme käytimme geneettisesti muunneltua HIF-P4H-2-hiirikantaa, joka tuottaa alentunutta määrää villityypin Hif-p4h-2 lähetti-RNA:ta kudoksissaan. Näille hiirille kehittyi ikäriippuvaisesti lievä punasoluylimäärä eli erytrosytoosi johtuen pernan kiihtyneestä punasolutuotannosta riippumatta seerumin erytropoietiinikonsentraatiosta. Lisäksi nämä hiiret olivat suojassa tulehduksen aiheuttamalta anemialta, joka on yleinen ilmiö tulehduksellisista sairauksista kärsivillä potilailla. HIF-P4H-2-muuntogeenisten hiirten lihasten energia-aineenvaihdunta oli muuttunut siten, että se yhdessä suurentuneen keskimääräisen kapillaaripinta-alan kanssa pienensi vaurioituneen kudoksen pinta-alaa alaraajaiskemia-altistuksen jälkeen. Nämä tutkimukset osoittavat, että lääkkeellinen HIF-P4H-2-entsyymin estäminen on mahdollinen uusi hoitomuoto erytropoietiinille resistenteissä anemioissa sekä alaraajojen valtimoahtaumataudissa
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Neitemeier, Sandra [Verfasser], and Carsten [Akademischer Betreuer] Culmsee. "Inhibitors of p53 and HIF-prolyl-4-hydroxylases provide mitochondrial protection in a model of oxytosis / Sandra Neitemeier. Betreuer: Carsten Culmsee." Marburg : Philipps-Universität Marburg, 2016. http://d-nb.info/1082347051/34.
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Peignon, Grégory. "Adhésion cellulaire et différenciation entérocytaire : rôle de la E-cadhérine ?" Paris 6, 2005. http://www.theses.fr/2005PA066344.
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Bossu, Jean-Pierre. "Régulation transcriptionnelle de l'expression du gène de l'apolipoprotéine A-II humaine par son premier intron et étude du facteur de transcription HNF-4 humain." Lille 1, 1995. http://www.theses.fr/1995LIL10143.
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L'étude de l'expression de l'apolipoprotéine A-II humaine est un des axes importants de recherche dans la lutte contre l'athérosclérose, cause importante de mortalité dans les pays industrialises, et permettra la mise au point de nouvelles thérapies. Dans ce but, nous avons étudié : la régulation du gène de l'apolipoprotéine A-II humaine par son premier intron : l'apolipoprotéine A-II est quantitativement la seconde protéine des lipoprotéines de haute densité. Sa transcription est contrôlée par une région activatrice située en amont du promoteur de son gène. Nous avons mis en évidence que le premier intron de ce gène se comporte comme un répresseur de la transcription. Cet intron renferme trois séquences de fixation de protéines nucléaires. Elles ont toutes trois une activité répressive et correspondent à des éléments de régulation négatifs. Ces éléments fixent des facteurs de transcription inconnus. Deux de ces éléments forment des complexes nucléoprotéiques présentant des caractéristiques physico-chimiques très similaires et lient des protéines nucléaires identiques ou fortement apparentées. Ils présentent aussi des structures similaires, sont placés en tandem et sont composés de deux éléments de séquence nécessaires à l'activité maximale et à la liaison optimale des facteurs de transcription. Le facteur de transcription HNF-4 (Hepatocyte Nuclear Factor 4) humain : HNF-4 est primordial pour la transcription de gènes exprimés dans le foie dont celui de l'apolipoprotéine A-II. Nous avons cloné l'acide désoxyribonucléique complémentaire de deux isoformes alpha 1 et alpha 2 codant pour le facteur HNF-4 humain. Dans la cellule hépatique humaine HEPG2, l'isoforme alpha 2 est prépondérante. Ces deux isoformes résultent d'un épissage alternatif.
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Winkel, Carmen. "Höchste Gerichtsbarkeit in Kriegszeiten : eine Tagung des Netzwerkes für Reichsgerichtsbarkeit, der Gesellschaft für Reichskammergerichtsforschung und des Haus-, Hof- und Staatsarchivs Wien; (Wien, 2. bis 4. April 2008)." Universität Potsdam, 2008. http://opus.kobv.de/ubp/volltexte/2008/2139/.
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Suaud, Laurence. "Le récepteur nucléaire HNF-4 humain : expression et activité de ses isoformes : études fonctionnelles de mutants associés à la forme MODY 1 du diabète non-insulino dépendant." Lille 1, 1998. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/1998/50376-1998-323.pdf.
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Le facteur de transcription hepatocyte nuclear factor-4 (hnf-4) appartient a la superfamille des recepteurs nucleaires d'hormones. Ces recepteurs possedent une structure en domaines. Il existe chez l'homme plusieurs isoformes de hnf-4 (1 a 6 et ). Hnf-4 joue un role preponderant dans l'embryogenese et dans la differenciation des cellules hepatiques. Il est aussi implique dans le metabolisme de nombreux composes dont les glucides. Des mutations dans le gene de hnf-4 sont associees a la forme mody 1 du diabete non insulino-dependant. En utilisant la cellule caco-2, modele representant la cellule epitheliale intestinale, nous avons montre que les isoformes de hnf-4 ont des taux d'expression differents et que la differenciation cellulaire s'accompagne d'une augmentation de l'expression d'un nombre limite d'isoformes de hnf-4. Ces isoformes different surtout par leur domaine f, qui est precisement le domaine qui module l'activite transcriptionnelle de hnf-4 et de son domaine d'activation af-2. L'etude des proprietes fonctionnelles (fixation a l'adn, transactivation, interactions avec d'autres recepteurs) de quatre mutants trouves chez les patients mody 1, a permis de definir plusieurs groupes de mutations : les mutations t130i et v255m n'ont aucun effet sur les proprietes fonctionnelles de hnf-4 et correspondent a des polymorphismes. Les mutations e276q et v393i provoquent une perte partielle de l'activite transactivatrice de hnf-4, mais la mutation e273q en affectant l'expression du facteur de transcription hnf-1, qui est important dans la glycemie, a des consequences cliniques typiques du mody. Les mutations donnant des formes tronquees de hnf-4 sont associees au mody 1 typique.
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Bonnyai, Samuel. "Innovation modes, determinants and policy effectiveness : a firm level empirical study using the UK CIS 4, 5 and 6." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4689/.
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This thesis makes use of recently collected UK Community Innovation Survey data to investigate 3 areas that allow to characterise and thus understand more clearly the innovation process in the UK. Firstly strategies of innovation used by firms are identified. Next the determinants of innovation, that is factors driving innovation inputs and outputs, are estimated. Thirdly this work examines the effectiveness of financial public support towards innovation. This also allows to establish which firms are more likely to be in receipt of public support and thus whether government innovation policy is in line with its objectives. Furthermore in this thesis a measure of absorptive capacity for the CIS is created, to see whether this proxy contributes in explaining innovative activities and the receipt of public support towards innovation. Similarly a measure of appropriability is generated for use as an explanatory variable in the estimation of the determinants of innovation. Both of these measures permit to find out if their latent variables have nonlinear effects in explaining propensity and extent of innovative spending. All these aspects have not received attention in previous literature, in large part due to the novelty of the data used. Besides the empirical evidence gained on the above, the addition to the literature of this thesis lies in examining several CIS survey rounds together. For one this serves as a robustness check for the conducted applications and on the other hand it allows investigating the comparability of the survey rounds. For this work the CIS 4, the CIS 5 and the CIS 6 are used as they are the most similar and comparable samples of UK businesses to date. Nevertheless it was found that differences in terms of design, wording and exclusion of responses to some question sets in the different surveys impedes their use for trend analysis and panel data analysis. Something the data collecting agencies need to address in the future. Despite these issues the conducted investigation has provided useful insights into innovation as it takes place in the UK. The first empirical chapter has been able to identify two major modes of innovation as captured by the survey. A ‘traditional’ or ‘linear’ strategy aimed at introducing product and process innovations, relying on innovative activities such as R&D and also making use of sources of information, more strongly from market sources then from science sources. Secondly a ‘dynamic’ or ‘systemic’ strategy also involving innovative activities such as R&D but more strongly making use of knowledge sources from science as well as relying on cooperation. The interpretation of this “blue skies strategy” which is not directly linked to achieving technological outputs is that it generates knowledge that helps to keep abreast of market developments and to be ready to spot opportunities in line with the literature on dynamic capabilities thus the identified strategies allow for a plausible interpretation congruent with innovation theory. In this chapter the aforementioned measure of appropriation and absorptive capacity were also successfully generated. These were then shown to play a significant role in explaining innovative activities in the subsequent empirical chapter, both exhibiting decreasing returns to scale. Following the CDM methodology this work has confirmed that knowledge capital as proxied by predicted R&D spending intensity is as important in generating service innovations as it is in stimulating goods innovations for the UK. The results also show that absorptive capacity not only indirectly impacts the likehood of introducing service innovations through its effect on knowledge capital as for goods innovations but also directly. This suggests that services once conceived further have to be tailored to individual customer’s needs. Hence absorptive capacity is specifically important in a developed economy dominated by service sector industries. At the same time the fit of the models confirmed that the CIS could do better at explaining service and process innovations by soliciting more information that are likely to cause these types of innovation. Finally further support for the innovation productivity nexus has been found. The last empirical chapter then established that absorptive capacity is also an important factor explaining the likehood of firms to be in receipt of financial public support towards innovation. This chapter further concluded that the financial public support towards innovation in the UK has in the recent past been effective at stimulating innovative performance besides just R&D spending. The government’s objective of supporting start-ups, that potentially face difficulties in financing their innovative activities, as well as supporting cooperation, vital for the dissemination of knowledge in the economy, is met according to the results. However SMEs could not be shown to be statistically more likely to be in receipt of public support despite facing the same problems as start-ups, though at least they are not less likely to be in receipt of public support then large firms. This finding stipulates that policy objectives are not achieved with regard to specifically targeting SMEs.
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Hansmannel, Franck. "Régulation de l'expression du gène de la thiolase B peroxysomale de rat : activation par les proliférateurs de peroxysomes, interférence avec le récepteur HNF-4, répression par les stérols." Dijon, 2004. http://www.theses.fr/2004DIJOS018.
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La 3-cétoacyl-CoA thiolase peroxysomale catalyse la dernière étape de la b-oxydation des acides gras dans le peroxysome. Son expression est régulée au niveau transcriptionnel par le récepteur nucléaire PPARa et des hypolipémiants appelés proliférateurs de peroxysomes. Cette régulation nécessite la présence dans le promoteur des gènes cibles d'un élément de réponse spécifique appelés PPRE. Chez le rat, il existe 2 isoformes de la thiolase, codées par 2 gènes différents (rTA et rTB). Seul rTB est inductible. Aucun PPRE fonctionnel n'a été localisé dans son promoteur. Aucune autre voie de régulation de l'expression du gène rTB n'a été étudiée. Nous avons identifié 2 PPRE fonctionnels, PPRE4 et PPRE2, dans l'intron 3 du gène rTB, qui coopèrent pour l'activation de l'expression génique. HNF-4 interfère avec PPARa au niveau de ces 2 PPRE. Enfin, nous avons mis en évidence l'existence d'une répression de l'expression du gène rTB par les stérols<br>The peroxisomal 3-ketoacyl-CoA thiolase catalyses the last step of the fatty acids breakdown in the peroxysome. Its expression is controlled at the transcriptional level by the nuclear receptor PPARa and hypolipidemic compounds called peroxisome proliferators. This regulation needs specific peroxisome proliferators responsive element (PPRE) in the promotor of the targeted genes. In rat 2 different genes (rTA et rTB) encode 2 isoforms of the peroxisomal 3-ketoacyl-CoA thiolase and only the rTB gene is inducible. No functional PPRE were found in the promotor of this gene. Peroxisome proliferators activation pathway is the only one never studied. We identified 2 functional PPRE in the sequence of the intron 3 of the rTB gene, which cooperate to mediate the PPARa effect. HNF-4 modulates the effect of PPARa and of peroxisome proliferators through those 2 PPRE. Finally, we established the evidence of a repression of the rTB by sterols
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Cheurfa, Nadir. "Implication de 5 gènes candidats exprimés dans les cellules bêta-pancréatiques dans les déterminants génétiques du diabète de type 2 et de ses complications vasculaires." Paris 7, 2007. http://www.theses.fr/2007PA077196.
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Les travaux de recherches qui ont conduit à la préparation de ce manuscrit s'inscrivent dans le cadre de l'exploration des déterminants génétiques du diabète de type 2 et de ses complications vasculaires. Nous avons étudié 5 gènes candidats régulateurs connus ou supposés de la sécrétion d'insuline (WFS1, PERK, LPK, UCP2, Coup-TFII), exprimés dans la cellule β-pancréatique. Nous avons observé une association très significative entre le diabète et des variations alléliques du gène WFS1 dans l'étude prospective DESIR. Cette association était confirmée dans deux autres cohortes indépendantes (DIABHYCAR et NCH). Nous rapportons également une association du variant fonctionnel -866G>A du promoteur d'UCP2 avec le risque de maladie coronarienne chez les diabétiques de type 2 (étude prospective DIABHYCAR, étude transversale NCH). Dans les deux cohortes, l'allèle A (associé à une augmentation de l'expression d'UCP2) était associé à une diminution de 12-20% du risque coronarien. Les variants alléliques des gènes PERK et L-PK ne semblent pas contribuer de façon importante aux déterminants génétiques du diabète de type 2. Nos résultats préliminaires suggèrent que des mutations de COUP-TFII ne seraient pas impliquées, ou du moins pas d'une façon fréquente, dans le diabète monogénique de type MODY<br>Researchs which drove to the preparation of this manuscript are part of the study of the genetic determinants of type 2 diabetes and its vascular complications. We studied 5 candidate genes supposed or known to be regulators of insulin secretion (WFS1, PERK, LPK, UCP2 and Coup-TFII), expressed in the β - pancreatic cell. We observed a very significant association between type 2 diabetes and allelic variants of WFS1 gene in the prospective study DESIR. This association was confirmed in two other independent cohorts (DIABHYCAR and NCH). We also reported an association between the - 866G> variant in the UCP2 promoter with coronary artery disease risk in subjects with T2DM (prospective study DIABHYCAR and cross-sectional study NCH). In both cohorts, the A-allele (associated with increased expression of UCP2) was associated with a reduction of 12-20 % of CAD risk. The allelic variants of PERK and L-PK genes are unlikely to contribute in an important manner in genetic determinants of type 2 diabetes. Our preliminary results suggest that mutations in COUP-TFH gene are also unlikely to contribute to the monogenic form of diabetes (MODY)
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Osafo, Joy Kwakyewaa. "Regulation of the V1 mRNA variant of the human growth hormone receptor gene by Gfi-1, Gfi-1b, a GAGA element and the liver enriched transcription factor, HNF-4[alpha]." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102688.
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GH acts through its specific receptor, GHR. In the human liver, more than twelve hGHR mRNAs are transcribed from unique TUTR exons, seven of which are found in two small clusters: module A (V2,V9,V3) and module B (V7,V1,V4,V8). While module A mRNAs are ubiquitously expressed, module B transcripts are restricted to normal postnatal liver, suggesting developmental- and liver-specific regulation of the hGHR gene. To begin characterising the elements regulating module B mRNA expression, I studied the promoter region of the V1 exon, the most abundantly expressing variant in liver. A 1.8 kb region upstream of the V1 transcriptional start site (TSS) was actively repressed in transient transfection assays (TTAs). However, T or 3' deletions relieved the suppression, suggesting the presence of multiple negative and positive regulatory elements. Two sites for growth factor independence-1 (Gfi-1) and Gfi-1b and a GAGA element were identified in the most 3' 300 by regulatory region. Gfi-1 was detected by western blot in human foetal and postnatal liver. Gfi-1 and Gfi-lb strongly repressed while the Drosophila GAGA factor (GAF) stimulated V1 transcription through their specific sites, as determined by TTAs and site-directed mutagenesis (SDM). Six putative sites for hepatic nuclear factor-4 (HNF-4) were also identified in the 1.8 kb region. HNF-4alpha is developmentally regulated in human liver: HNF-4alpha,2 and alpha8 proteins are expressed in foetal hepatocytes but only HNF-4alpha2 is detected postnatally. TTAs and SDM demonstrated that HNF-4alpha2 and HNF-4alpha8 have a similar dual effect on V1 transcription: activation via site #1 in the proximal promoter and repression through site #6, ~1.7 kb upstream of the TSS. Results from EMSA/EMSSA/ChIP analyses suggest these sites are bound by HNF-4alpha.<br>Thus, V1 transcriptional activity is repressed by Gfi-1/Gfi-1b, stimulated through a GAGA element by GAF, and repressed or stimulated by HNF-4alpha. (2+8) depending on the site. Similar sites are present in homologous regions of the bovine, ovine and mouse GHR genes suggesting that their regulatory roles are conserved. However, none of these factors individually appear to be responsible for the postnatal hepatic-specific expression of V1 mRNA. To define the specific regulatory mechanisms, future studies should examine their interactions with additional liverenriched factors (e.g. C/EBPalpha).
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Vieira, Mathieu. "Régulation de l'expression du gène Nodal lors de la différenciation des cellules souches embryonnaires." Thesis, Sorbonne Paris Cité, 2018. https://theses.md.univ-paris-diderot.fr/VIEIRA_Mathieu_2_va_20180930.pdf.
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L'influence des signalisations ACTIVINE/NODAL et FGF sur les cellules souches embryonnaires murines (mESC) déclenchent leurs différenciations en cellules analogues aux EpiSC (EpiLCs). Cette différenciation modifie les niveaux d'expression des facteurs de pluripotence et il va promouvoir un changement global de l'expression génique. C'est notamment le cas pour le gène Nodal. Alors que son expression est dépendante des facteurs de transcription liés à son enhancer HBE dans les mESCs, il devient principalement dépendant de sa boucle de rétro-contrôle positive médiée par l'enhancer ASE (dépendant de la signalisation ACTIVINE/NODAL) dans les EpiLCs. De précédentes études effectuées au laboratoire ont mis en évidence que les mESCs où HBE a été enlevé sont incapables d'exprimer Nodal une fois différenciées en EpiLCs, démontrant que, bien qu'HBE ne soit pas nécessaire à l'expression de Nodal en EpiLC, sa présence est requise en mESC pour assurer l'expression ultérieure de Nodal en EpiLC (Papanayotou et al 2014). Cette découverte soulève la question de savoir si HBE exerce son contrôle directement sur ASE ou bien via d'autres régions régulatrices du locus. On peut également se demander par quels intermédiaires moléculaires (changements chromatiniens) se contrôle à lieu et quels sont les facteurs impliqués (modificateurs ou remodeleurs de la chromatine, facteurs de pluripotence). Pour répondre à ces questions j'ai tout d'abord généré des délétions spécifiques de HBE et ASE dans les mESCs en utilisant l'outil d'édition génétique CRISPR/Cas9. J'ai ensuite caractérisé l'impact de ces délétion sur l'expression de Nodal par RT-qPCR et imagerie en temps réel d'un rapporteur NodalcondHBE-YFP endogène. Alors que HBE est essentiel à l'expression de Nodal en mESC j'ai également découvert que ASE contribue à l'expression de Nodal dans ces cellules. Pour disséquer le fonctionnement de HBE j'ai généré des lignées de mESCs manquant des régions de HBE qui sont conservé chez les mammifères. L'impact de ces délétions m'ont permis d'identifier le domaine HBE2 comme étant responsable de l'activité transcriptionnelle de HBE dans les mESCs. Ce domaine contribue également à l'activité de Nodal dans les EpiLCs, démontrant que bien que HBE ne soit pas essentiel à l'expression de Nodal en EpiLC, il participe tout de même à son expression. Aucun domaine de HBE ne semble être seul responsable du contrôle de l'activation de l'ASE dans les EpiLCs. Cette fonction semble ainsi être distincte de l'activité transcriptionnelle de HBE. Une analyse par ChIP-qPCR dans les mutants HBE-/- et ASE-/- ont révélé que les modifications d'histones présentes sur le promoteurs et sur ces enhancers étaient différentes. Ces données nous laissent envisager que la maintenance du paysage épigénétique du locus Nodal implique des interactions entre ces différents éléments régulateurs. L'analyse de différentes données d'immuno-précipitation de la chromatine ont mis en évidence une liste de facteurs de transcription recrutés au locus Nodal. Différents éléments suggèrent que des facteurs de transcription présents sur ASE contrôlent son activité et sont affectés par la présence de HBE. Ce travail mets en lumière un mécanisme de régulation génique inédit. Ce travail est également un premier pas vers la mise en évidence d'un nouveau mécanisme responsable de la réorganisation de la régulation transcriptionnelle du génome au cours de la différenciation des mESCs en EpiLCs<br>Exposure of embryonic stem cells (mESCs) to ACTIVIN/NODAL and FGF signaling initiates their differentiation into EpiSC-like cells (EpiLCs). This exposure triggers changes in the expression levels of pluripotency factors, and promotes a global shift in gene expression. Remarkably, most of the genes that maintain their expression during this differentiation also undergo a shift in their regulation from one enhancer to another. This is notably the case of the Nodal gene itself. While its expression is dependent on pluripotency factors interacting with its enhancer HBE in mESCs, it is primarily dependent on its auto-regulatory (ACTIVIN/NODAL signaling-dependent) ASE enhancer in EpiLCs. Work in the lab has however shown that mESCs where HBE has been removed are unable to express Nodal once they are differentiated into EpiLCs, revealing that, although EpiLCs do not require HBE to express Nodal, its presence is required in mESCs to ensure later Nodal expression in EpiLCs (Papanayotou et al., 2014). One question raised by this finding is whether HBE exerts its control over Nodal expression solely via its interaction with the promoter or whether it involves HBE directly influencing ASE or other Nodal regulatory regions. Another concerns the nature of the molecular means (chromatin changes) deployed to exert this control and the identity of the factors involved (chromatin remodelers and modifiers, pluripotency factors). To answer these questions I first started to generate specific deletions of HBE and ASE in mESCs using CRISPR/Cas9-mediated genome-editing. I then characterized the impact of these deletions on Nodal expression using qPCR and live imaging of a knocked-in NodalcondHBE-YFP reporter. Although HBE is essential for Nodal expression in mESCs, I found that ASE also contributes to Nodal expression in these cells. To dissect HBE functions I generated mESC lines deleted for sequence conserved subdomains of HBE. Analysis of the impact of these deletions allowed me to find that only one of these subdomains, HBE2, is essential for HBE transcriptional activity in mESC. This subdomain also contributes to Nodal expression in EpiLCs, highlighting the fact that although HBE is not essential to Nodal expression in EpiLCs it does contribute to maintaining its level. However, in contrast to the deletion of the entire HBE, none of these subdomains deletions affected the ability of ASE to drive Nodal expression in EpiLCs, indicating that the distinct functions of HBE in the regulation of Nodal expression can be experimentally dissociated and their molecular basis investigated. Furthermore, ChIP-qPCR analyses revealed that the deletion of HBE or ASE both affected histone mark profiles at the promoter and at the other regulatory element, supporting the view that the maintenance of the epigenetic landscape at the Nodal locus involves multiple interactions between its various regulatory elements. The analysis of ChIP-seq datasets and ChIP-qPCR results has allowed me to compile a list of transcription factors known to bind the Nodal locus. Interestingly, key transcription factors controlling ASE activity could be affected by the presence of HBE. This work unfolds a novel mechanism of gene regulation involving enhancer interaction. This thesis is also the first step towards revealing a new mechanism at place during the reorganization of the transcriptional landscape during mESC to EpiLC differentiation
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Tagro, Yoann. "Mise au point d’une méthodologie de caractérisation des 4 paramètres de bruit HF des technologies CMOS et HBT avancées dans la bande 60-110 GHz : développement de système à impédance variable in-situ." Thesis, Lille 1, 2010. http://www.theses.fr/2010LIL10123/document.
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Les avancées technologiques sur la réduction de la longueur de grille en accord avec la loi de Moore permettent aujourd’hui d’avoir des transistors sur silicium assez performants (ft/fMax > 150 GHz). La connaissance des performances dynamiques et en bruit en gamme millimétrique des transistors passe par leur caractérisation qui aujourd’hui est rendue difficile à cause de la limitation en fréquence des appareils de mesure. Il a été question dans cette thèse d’établir dans un premier temps un état de l’art sur les tuners d’impédances. Cette étude a débouché sur la nécessité de concevoir et de caractériser des tuners intégrés pour s’affranchir des pertes d’insertions causées par les dispositifs passifs entre les tuners mécaniques et les transistors sous test. Nous avons décrit les BEOL et les différents composants constituant le tuner intégré, puis définit une architecture commune aux 2 technologies CMOS 65 nm et BiCMOS9MW. La mesure des tuners présente des performances meilleures (TOS de 7 :1 et 150 :1) que les tuners mécaniques standards. Les méthodes de caractérisation en bruit sont présentées avec une attention particulière sur la méthode des impédances multiples que nous avons utilisée en source froide. Nous concluons par l’extraction des 4 paramètres de bruit des transistors MOSFET et HBT, en utilisant les tuners intégrés conçus. Les performances obtenues sont respectivement de l’ordre de 2 dB et 3.5 dB à 80 GHz et sont en accord avec les modèles utilisés. Une ouverture vers des applications encore plus larges des tuners est présentée, permettant d’envisager des applications au-delà de la bande W (75-110 GHz), des systèmes load-pull et des amplificateurs à gain variable<br>The advanced technologies following the gate length scaling in agreement with Moore’s law allow today to get high performances of silicon transistors (ft/fMax > 150 GHz). The knowledge of the silicon transistors’ dynamic and noise performances in millimeter wave range is mandatory but they characterization is difficult due to the limitation of measurement tools. In this thesis we establish in a first step a state of the art of existing impedance tune. This study is followed by the design and the characterization of integrated impedance tuners in order to avoid the insertion losses induced by the passive devices between mechanical tuner and transistors under test in classical setup. We have described the BEOL, the different integrated tuner’s components, and defined a common tuner’s architecture for both technologies (CMOS 65 nm and BiCMOS9MW). The tuner measures presented performances (TOS of 7:1 and 150:1) better than mechanical ones. The noise characterization methods are presented with particular focus on the multi impedance method that we have used in cold-noise source. We conclude by the extraction of the 4 noise parameters of the MOSFET and HBT transistors, using designed integrated tuners. The obtained noise performances in millimeter wave range are respectively around 2 dB (MOSFET) and 3.5 dB (HBT) and are in agreement with the used models. The possibility to address a broad band of applications with these tuners is also presented, such as load-pull applications, G band integrated tuner, variable gain amplifier
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Masselli, dos Reis Ivan Gustavo 1983. "Efeito agudo do exercício em intensidade equivalente e acima da máxima fase estável de lactato nas expressões proteicas e mRNAs de HIF-1a, MCTs 1 e 4 e PGC-1a, em tecido cardíaco, hepático e muscular esquelético de ratos nadadores." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/274683.
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Orientador: Claudio Alexandre Gobatto<br>Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Educação Física<br>Made available in DSpace on 2018-08-27T03:03:23Z (GMT). No. of bitstreams: 1
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Previous issue date: 2015<br>Resumo: Sabe-se que o estresse físico exerce uma função moduladora na expressão gênica dos MCTs 1 e 4 por meio de vias de sinalização moleculares aparentemente distintas envolvendo o co-ativador-1 'alfa' do receptor gama ativado por proliferador do peroxissomo (PGC-1?) e subunidade 1 'alfa' do fator induzível por hipóxia (HIF-1?) respectivamente. Apenas uma única sessão de exercício de resistência (endurance) está associada ao aumento na expressão do MCT1 e PGC-1?, mas não do MCT4, no músculo esquelético vasto lateral de humanos, enquanto o exercício intermitente de alta intensidade parece afetar ambos MCTs 1 e 4 além do PGC-1?. No entanto pouco se conhece sobre o efeito simultâneo do estresse físico sobre o HIF-1?, MCts 1 e 4 e PGC-1? em diferentes tecidos e tipos de fibra. É provável que tanto a expressão quanto a transcrição dos co-ativadores e fatores de transcrição envolvidos na modulação dos MCTs 1 e 4 frente ao estresse físico sejam afetadas pelas características da atividade e ainda variem de acordo com o tipo e especificidade do tecido analisado. Dessa forma, o objetivo desse estudo foi verificar o efeito agudo de uma única sessão de natação até exaustão ou de 30 minutos contínuos ou 25 minutos acumulados intermitentemente, em uma intensidade equivalente ou 20% superior a máxima fase estável de lactato, sobre a expressão gênica e conteúdo protéico dos HIF-1?, MCTs 1 e 4, PGC-1?, imediatamente, 2, 4 e 8 horas após a sessão de exercício, em tecidos chaves para metabolismo do lactato (fibras esqueléticas I e II, fígado, coração) de ratos. O exercício físico aumenta a expressão proteica e mRNA em relação ao grupo controle para maior parte dos genes que foram analisados, porém, não há diferenças entre os grupos exercitados independente do tecido e do protocolo utilizado. Com exceção do tecido hepático cuja apenas a expressão de PGC-1? mRNA é estimulada, uma única sessão de exercício induz diferentes respostas ao longo de 8 horas na expressão mRNA e conteúdo de HIF-1?, MCTs 1 e 4, PGC-1?. Uma sessão contínua de volume reduzido ou uma sessão intermitente em intensidade 20% superior a MFEL, resultam nas mesmas adaptações de uma sessão contínua de 30 minutos de duração em intensidade equivalente a MFEL<br>Abstract: It is known that physical stress plays a role on regulating the gene expression of MCTs 1 and 4 by distinct molecular signaling pathways involving the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1?) and hypoxia inducible factor 1 alpha subunit (HIF-1?) respectively. Only a single endurance session is associated with increased expression of both PGC-1? and MCT1, but not of the MCT4 in the muscle vastus lateralis of humans, while the intermittent exercise of high intensity seems to affect, besides the PGC-1?, both MCTs 1 and 4. However, the knowledge about the simultaneously effect of the exercise stress on the HIF-1?, MCTs 1 and 4 and PGC-1? in different types of tissues and skeletal muscles is unknow. Probably, the transcription factors and the coativators involved in the exercise induced modulation of MCTs 1 and 4 can being differently affected by the exercise intensity and may vary according to the type and metabolic specificity of the tissue. Thus, the aim of this study was to investigate the acute effect of a single swimming session of 30 continuous minutes or 25 minutes accumulated intermittently or until exhaustion in the intensity equivalent or 20% higher than the maximum lactate steady state (MLSS), on the gene expression and protein content of HIF-1?, MCTs 1 and 4, PGC-1?, immediately, 2, 4 and 8 hours after, in key tissues to the lactate metabolism (skeletal muscle of type I and II, liver, heart) of rats. Physical exercise increased protein content and mRNA expression for most of the analyzed genes, however, there are no differences between the exercised groups independently of the tissue or protocol used. With the exception to liver, where only PGC-1? mRNA was stimulated, a single exercise bout induced different responses throughout 8 hours on mRNA expression and content of HIF-1?, MCTs 1 and 4, PGC-1?. Both, continuous or intermittent exercise, of reduced volume and in higher intensity (20%) results in similar responses of a continuous session of 30 minutes duration in the MLSS intensity<br>Doutorado<br>Biodinamica do Movimento e Esporte<br>Doutor em Educação Física
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Torre, Cyril. "Analyse haut-débit des complexes transcriptionnels de la β-caténine dans le foie murin". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T004/document.
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La voie Wnt/β-caténine est impliquée dans la prolifération et le contrôle du destin cellulaire de nombreux tissus à la fois au cours du développement et pour le maintien de l’homéostasie chez l’adulte. L’équipe a montré qu’une activation aberrante de la β-caténine conduisait au développement de carcinomes hépatocellulaires (CHC), alors que son activation physiologique dans une souspopulation d'hépatocytes du foie adulte (les hépatocytes éricentraux) permet la mise en place et le maintien du zonage métabolique. Ce zonage hépatique peut être considéré comme une différenciation terminale des hépatocytes, et permet au foie d'être pleinement fonctionnel. L’objet de ma thèse a été d’identifier les déterminants moléculaires expliquant la diversité d’action de la β-caténine dans le foie. J'ai tiré profit de modèles génétiques développés au laboratoire d'activation ou d'inactivation inductibles de la voie β-caténine dans le foie. A partir d'hépatocytes isolés de ces modèles, j'ai recherché par ChIp-seq (immunoprécipitation de chromatine couplée à un séquençage haut-débit) les sites de fixation sur l’ADN de la β-caténine et de Tcf4, que j'ai identifié comme principal médiateur de l’activité nucléaire de la β-caténine dans le foie. Ces données, couplées à des études d’accessibilité de la chromatine et de transcriptome ont permis d’identifier la structure de la chromatine et Hnf4a comme déterminants majeurs permettant à la beta-caténine de contrôlerpositivement et négativement des programmes génétiques spécifiquement hépatiques, qui luipermettent d'assurer le zonage métabolique du foie. En effet, Hnf4a a un rôle antagoniste de la β-caténine, contrôlant positivement la transcription des gènes réprimés par la β-caténine. Ce contrôles'exerce grâce à un dialogue d'Hnf4a avec Tcf4 et la β-caténine, qui s'opère majoritairement via des interactions entre ces protéines. Nous proposons ainsi que la β-caténine coopère avec le facteur de transcription Hnf4a, connu pour contrôler les gènes du métabolisme hépatocytaire, pour assurer la différenciation terminale hépatique. J'ai également recherché les partenaires protéiques nucléaires de la β-caténine par coimmunoprécipiatation couplée à de la spectrométrie de masse. Plusieurs protéines jouant un rôle dans l'épissage des ARN ont pu être identifiées de cette manière. La quantification exon par exon des transcrits séquencés par RNA-Seq m'ont également permis d'identifier une possible régulation directede l’épissage des gènes SLC39A14 et NDRG2 par la β-caténine. Enfin, nous nous sommes attachés à comprendre comment la β-caténine jouait un rôle prolifératif suite à son activation aberrante dans le foie d'une part (par l'utilisation d'un modèle transgénique prénéoplasique) et lors de la régénération hépatique d'autre part. Nous avons pu démontré que ce rôle prolifératif était complexe, seulement partiellement autocrine, mettant en jeu la Cycline D1 et le facteur de croissance Tgfa, que nous avons définis comme étant des cibles directes de la β-caténine dans le foie. Ces derniers résultats évoquent également un dialogue fonctionnel entre la voie β-caténine et la cascade de signalisation Tgfa-Egf/Egfr/Erk pour assurer la prolifération hépatocytaire<br>The Wnt/β-catenin pathway is involved in proliferation and cell fate control and regulatesdevelopmental stages as well as adult tissue homeostasis. Our team has previously shown that aberrantB-catenin signaling induced Hepatocellular Carcinoma (HCC) development, whereas physiologicalactivation in a subpopulation of adult liver hepatocytes (pericentral hepatocytes) patterns liverzonation. This hepatic zonation can be considered as hepatocytes terminal differenciation.My thesis aimed to identify key molecular determinants allowing diversity upon β-catenin activation.I took advantage of genetically engineered mice models of activation or inactivation of β-catenin,developped in the laboratory. Using hepatocytes obtained from these models I identified β-catenin andTcf4, that I previously identifed as the main effector of nuclear β-catenin in liver, binding sites byChIp-seq (Chromatin Immunoprecipitation followed by high-throughput sequencing). Couplingbinding site localization to transcriptomic and chromatin accessibility studies allowed to identifychromatin structure and tissue specific transcription factor HNF4A as key modulators of β-cateninsignaling in the liver and therefore modulators of metabolic zonation. Indeed, β-catenin negativelyregulates Hnf4a target genes. This negative control exerts essentially via protein interactions. Wepropose that β-catenin and Hnf4a cooperates to ensure terminal hepatic differenciation.I also searched for nuclear β-catenin partners by co-immunoprecipitation followed by massspectrometry. This approach revealed many splicing factors as beta-catenin partners. RNA seqanalysis revealed a possible direct regulation of splicing of SL39A14 and NDRG2 genes.Finally we tried to understand the proliferative role of β-catenin during liver regeneration. Wedemonstrated a complex and partially autocrine role of B-catenin. We defined CyclinD1 and thegrowth factor Tgfa as β-catenin direct targets in the liver. These latest results also imply a functionnaldialog between the β-catenin pathway and Tgfa-Egf/Egfr/Erk signalisation cascade to allowhepatocytes proliferation
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Perilhou, Anaïs. "Le facteur de transcription COUP-TFII, un nouvel acteur dans le contrôle de l'homéostasie glucidique dans le foie et le pancréas." Paris 5, 2008. http://www.theses.fr/2008PA05T028.
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La régulation de l'homéostasie glucidique est notamment contrôlée au niveau génique. Nous avions montré que la délétion de COUP-TFII (Chicken ovalbumin upstream promoter transcription factor II) dans les cellules insuliniques chez la souris entraîne un défaut de sécrétion d'insuline. Ce travail montre que 1) l'expression de COUP-TFII est contrôlée négativement par le glucose et l'insuline dans les cellules bêta du pancréas et les hépatocytes in vivo et in vitro via la signalisation des facteurs ChREBP et Foxo-1; 2) COUP-TFII inhibe la transcription, le contenu et la sécrétion d'insuline et Festérifïcation des acides gras dans la lignée de cellules bêta INS-1 832/13; 3) il existe une activation réciproque entre l'expression des gènes COUP-TFII et HNF-4α (MODY-1) dans les cellules bêta. Ces résultats permettent de proposer COUP-TFII comme une acteur majeur dans le contrôle de l'homéostasie glucidique à jeun, et donc potentiellement dans des pathologies comme le diabète de type 2<br>Metabolic pathways concerned in the regulation of glucose homeostasis in liver and pancreas are precisely controlled at gene level. We showed that COUP-TFII (Chicken ovalbumin upstream promoter transcription factor II) deletion from pancreatic beta cells in heterozygous mice led to abnormal insulin secretion. This work reveals that 1) COUP-TFII expression is negatively controlled by glucose and insulin in pancreatic beta cells and hepatocytes, in vivo and in vitro, via ChREBP and Foxo-1 signaling; 2) COUP-TFII inhibates insulin genes transcription, as well as insulin content and insulin secretion in beta 832/13 ENS-1 cell line, and decreases the fatty acid esterification capacity in these cells; 3) COUP-TFII and HNF-4alpha (MODY-1) activate one another their expression in pancreatic beta cells. These results conduct and argue to propose an important contribution of COUP-TFII hi the control of glucose homeostasis in the fasted state, and potentially in pathologies as type 2 diabetes
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Thomas, Amandine. "Hypoxie intermittente et homéostasie glucidique : étude des mécanismes d'action cellulaire A hybrid model to study pathological mutations of the human ADP/ATP carriers Visceral white fat remodeling contributes to intermittent hypoxia-induced atherogenesis The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system The Impact of Sleep Disorders on Glucose Metabolism: Endocrine and Molecular Mechanisms Endoplasmic reticulum stress as a novel inducer of hypoxia inducible factor-1 activity: its role in the susceptibility to myocardial ischemia-reperfusion induced by chronic intermittent hypoxia Chronic intermittent hypoxia improves whole-body glucose tolerance by activating skeletal muscle AMP-activated protein kinase in mice Prolyl-4-hydroxylase 1 (PHD1) deficiency impairs whole-body glucose tolerance and insulin sensitivity in mice but does not worsen high-fat diet-induced metabolic dysfunctions Specific transcriptomic signature in response to intermittent hypoxia exposure in liver and fat tissue." Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GREAV044.
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L'hypoxie intermittente (HI), induite par les apnées du sommeil, conduit à des altérations de la sensibilité à l'insuline et de l'homéostasie glucidique mais les mécanismes impliqués restent mal connus. L'objectif de ce travail était d'étudier les effets et les mécanismes sous jacents d'une exposition chronique à l'HI sur l'homéostasie glucidique. L'HI induit une résistance à l'insuline à la fois systémique et tissulaire, ainsi qu'une amélioration de la tolérance au glucose associée à une activation de l'AMPK musculaire. L'HI cause également des altérations du foie et du tissu adipeux associées à un changement du pattern d'expression des gènes dans ces tissus et à un risque accru de développement de pathologies vasculaires comme l'athérosclérose. Enfin, la délétion de PHD1, une des protéines régulatrices de HIF-1, entraîne une résistance à l'insuline associée une stéatose hépatique, faisant de HIF-1 une cible potentielle impliquée dans les altérations metaboliques induites par l'HI<br>Intermittent hypoxia (IH), induced by sleep apnea, leads to alterations in insulin sensitivity and glucose homeostasis but the mechanisms involved remains poorly understood. The objective of this work was to study the effects and the underlying mechanisms of chronic exposure to IH on glucose homeostasis. IH induces both systemic and tissue-specific insulin resistance , as well as improved glucose tolerance associated with an activation of muscle AMPK. IH also causes a change in the pattern of gene expression in liver and adipose tissue and an increased risk of vascular pathologies such as atherosclerosis development. Finally, the deletion of PHD1, a regulatory protein of HIF-1, leads to insulin resistance associated with hepatic steatosis, making HIF-1 a possible target involved in the metabolic changes induced by IH
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SALCEDO, Javier. "DESIGN AND CHARACTERIZATION OF NOVELDEVICES FOR NEW GENERATION OF ELECTROSTATICDISCHARGE (ESD) PROTECTION STRUCTURES." Doctoral diss., University of Central Florida, 2006. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/2812.
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The technology evolution and complexity of new circuit applications involve emerging reliability problems and even more sensitivity of integrated circuits (ICs) to electrostatic discharge (ESD)-induced damage. Regardless of the aggressive evolution in downscaling and subsequent improvement in applications' performance, ICs still should comply with minimum standards of ESD robustness in order to be commercially viable. Although the topic of ESD has received attention industry-wide, the design of robust protection structures and circuits remains challenging because ESD failure mechanisms continue to become more acute and design windows less flexible. The sensitivity of smaller devices, along with a limited understanding of the ESD phenomena and the resulting empirical approach to solving the problem have yielded time consuming, costly and unpredictable design procedures. As turnaround design cycles in new technologies continue to decrease, the traditional trial-and-error design strategy is no longer acceptable, and better analysis capabilities and a systematic design approach are essential to accomplish the increasingly difficult task of adequate ESD protection-circuit design. This dissertation presents a comprehensive design methodology for implementing custom on-chip ESD protection structures in different commercial technologies. First, the ESD topic in the semiconductor industry is revised, as well as ESD standards and commonly used schemes to provide ESD protection in ICs. The general ESD protection approaches are illustrated and discussed using different types of protection components and the concept of the ESD design window. The problem of implementing and assessing ESD protection structures is addressed next, starting from the general discussion of two design methods. The first ESD design method follows an experimental approach, in which design requirements are obtained via fabrication, testing and failure analysis. The second method consists of the technology computer aided design (TCAD)-assisted ESD protection design. This method incorporates numerical simulations in different stages of the ESD design process, and thus results in a more predictable and systematic ESD development strategy. Physical models considered in the device simulation are discussed and subsequently utilized in different ESD designs along this study. The implementation of new custom ESD protection devices and a further integration strategy based on the concept of the high-holding, low-voltage-trigger, silicon controlled rectifier (SCR) (HH-LVTSCR) is demonstrated for implementing ESD solutions in commercial low-voltage digital and mixed-signal applications developed using complementary metal oxide semiconductor (CMOS) and bipolar CMOS (BiCMOS) technologies. This ESD protection concept proposed in this study is also successfully incorporated for implementing a tailored ESD protection solution for an emerging CMOS-based embedded MicroElectroMechanical (MEMS) sensor system-on-a-chip (SoC) technology. Circuit applications that are required to operate at relatively large input/output (I/O) voltage, above/below the VDD/VSS core circuit power supply, introduce further complications in the development and integration of ESD protection solutions. In these applications, the I/O operating voltage can extend over one order of magnitude larger than the safe operating voltage established in advanced technologies, while the IC is also required to comply with stringent ESD robustness requirements. A practical TCAD methodology based on a process- and device- simulation is demonstrated for assessment of the device physics, and subsequent design and implementation of custom P1N1-P2N2 and coupled P1N1-P2N2//N2P3-N3P1 silicon controlled rectifier (SCR)-type devices for ESD protection in different circuit applications, including those applications operating at I/O voltage considerably above/below the VDD/VSS. Results from the TCAD simulations are compared with measurements and used for developing technology- and circuit-adapted protection structures, capable of blocking large voltages and providing versatile dual-polarity symmetric/asymmetric S-type current-voltage characteristics for high ESD protection. The design guidelines introduced in this dissertation are used to optimize and extend the ESD protection capability in existing CMOS/BiCMOS technologies, by implementing smaller and more robust single- or dual-polarity ESD protection structures within the flexibility provided in the specific fabrication process. The ESD design methodologies and characteristics of the developed protection devices are demonstrated via ESD measurements obtained from fabricated stand-alone devices and on-chip ESD protections. The superior ESD protection performance of the devices developed in this study is also successfully verified in IC applications where the standard ESD protection approaches are not suitable to meet the stringent area constraint and performance requirement.<br>Ph.D.<br>School of Electrical Engineering and Computer Science<br>Engineering and Computer Science<br>Electrical Engineering
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Boutant, Marie. "Fonction et régulation du facteur de transcription COUP-TFII dans les cellules β du pancréas". Paris 5, 2011. http://www.theses.fr/2011PA05T047.
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La plasticité du pancréas endocrine est essentielle pour répondre de façon adaptée à une demande accrue en insuline et maintenir un contrôle optimal de l’homéostasie glucidique. L’invalidation génique de COUP-TFII dans les cellules ß pancréatiques à l’état hétérozygote chez la souris adulte conduit à une intolérance au glucose suite à une diminution de la sécrétion d’insuline en réponse au glucose. De plus, l’expression transcriptionnelle de COUP-TFII est inhibée par l’insuline. Au cours de cette thèse, l’étude des souris homozygotes et de la lignée cellulaire INS-1 832/13 nous a permis de mettre en évidence que COUP-TFII participe au maintien du nombre de cellules ! au cours de la période post-natale en activant la voie de signalisation Wnt/ß-caténine/TCF7L2 en réponse au GLP-1. Nous avons aussi mis en évidence une région du promoteur COUP-TFII activée par liaison d’HNF4 !MODY1 en réponse à de faibles concentrations de glucose. La diminution de COUP-TFII en réponse à de fortes concentrations de glucose implique la diminution d’HNF4" dont l’expression génique est sous le contrôle de la voie de signalisation de FOXO1, facteur réprimé par l’insuline. Enfin, nous avons établi une corrélation entre le polymorphisme rs3743462-C situé dans les régions régulatrices amont du gène COUP-TFII et des paramètres glucidiques liés à la sensibilité à l’insuline chez l’homme. Dans la cellule ß, ce variant lie COUP-TFII avec une plus grande affinité et est associé à une diminution de l’expression basale de COUP-TFII conduisant à une plus forte répression par le glucose. L’ensemble de ces données suggèrent que COUP-TFII participe in vivo à l’homéostasie glucidique de la souris et de l’homme<br>The development and maintenance of functional pancreatic β cell mass are essentials for an appropriate response to changes in blood glucose levels. Pancreatic β cell knockout of the COUP-TFII (Chicken Ovalbumin Upstream Promoter Transcription Factor II) gene, in adult heterozygous mice, led to glucose intolerance due to an impaired glucose-stimulated insulin secretion. We also reported that COUP-TFII expression is repressed by insulin. During this PhD, using COUP-TFII homozygous knockout mice and the 832/13 INS-1 β cells, our results suggested that COUP-TFII can provide sufficient stimulation of the Wnt/β-catenin/TCF7L2 dependent transcription signaling pathway in response to GLP-1 to allow development of an appropriate β cell mass during the postnatal period. We also identified a DNA region of the promoter that down-regulates COUP-TFII expression by attenuating the activating effect of HNF4 !MODY1 in response to high glucose concentrations through FoxO1 signaling, a major downstream target of the insulin signaling pathway. Finally, individuals from the prospective DESIR cohort carrying the minor C-allele at rs3743462 which is located in these conserved upstream regulatory regions, displayed lower basal levels of circulating insulin and a lower insulin resistance index. In β cells, this polymorphism is associated with a decreased of basal level of COUP-TFII gene activation and an increased repression to high glucose concentrations. We showed that COUP-TFII binds the rs3743462-C oligonucleotide with higher affinity suggesting a possible autorepression of its expression. In conclusion, COUPTFII could be a key regulator of in vivo glucose homeostasis in mice and in human
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Schultz, Anne-Kathrin. "Improvement of the jpHMM approach to recombination detection in viral genomes and its application to HIV and HBV." Doctoral thesis, 2011. http://hdl.handle.net/11858/00-1735-0000-0006-B3EA-4.
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Hölscher, Marion. "Cardiac functions of the cellular oxygen sensors prolyl-4-hydroxylase domain enzymes 2 and 3." Doctoral thesis, 2012. http://hdl.handle.net/11858/00-1735-0000-000D-EF6B-F.
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Brucz, Kimberly Anne. "HIF prolyl 4-hydroxylase (PHD) activity and the structure analysis blueprints for development of specific substrate inhibitors /." 2005. http://wwwlib.umi.com/dissertations/fullcit/1426751.
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Thesis (M.S.)--State University of New York at Buffalo, 2005.<br>Title from PDF title page (viewed on Feb. 3, 2006) Available through UMI ProQuest Digital Dissertations. Thesis adviser: L. Wayne Schultz. Includes bibliographical references.
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Brökers, Nils. "Chemoresistenz als Folge einer Inhibition der zellulären Sauerstoffsensoren (Prolyl-4-Hydroxylase-Domäne)." Doctoral thesis, 2010. http://hdl.handle.net/11858/00-1735-0000-0006-B287-8.
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Pektas, Serap. "O2 Activation and Allosteric Zn(Ii) Binding on Hif-Prolyl Hydroxylase-2 (Phd2)." 2013. https://scholarworks.umass.edu/open_access_dissertations/828.
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Oxygen homeostasis is essential to the life of aerobes, which is regulated in humans by Hypoxia Inducible Factor-1α (HIF-1α). Under hypoxic conditions, HIF-1α transactivates over a hundred genes related angiogenesis, erythropoiesis, etc. HIF-1α level and function is regulated by four HIF hydroxylase enzymes: three isoforms of prolyl hydroxylase domain (PHD1, PHD2 and PHD3) and factor inhibiting HIF-1α (FIH). PHD2 is the focus of this research. PHD2 is a non-heme Fe(II) 2-oxoglutarate dependent dioxygenase, which controls HIF-1α levels by hydroxylating two proline residues within the ODD domain of HIF-1α, then the hydroxylated prolines are recognized by pVHL, which targets HIF-1α for proteasomal degradation. Under hypoxic conditions PHD2 cannot hydroxylate HIF-1α and its level rises in cells. The aims of this research include understanding how PHD2 chooses its substrate, how the O2 activation occurs, and how certain transition metals inhibit PHD2.
Our results revealed that electrostatics play a role in substrate selectivity of PHD2 by provoking a change in the opening and closing rate of β2β3 loop for NODD and CODD substrates. Mutational studies of second coordination sphere residues combined with kinetic studies indicated that decarboxylation of 2OG is the slow step in the chemical mechanism. The removal of a hydrogen-bond by the Thr387aAla mutation revealed a rate 15 times faster than WT-PHD2 by making O2 a better nucleophile. Our results indicate that this hydrogen bonding is essential for proper O2 activation.
Previous reports show that certain metals increase HIF-1α levels by inhibiting PHD2. However there are conflicts about how this inhibition occurs, either through metal replacement from the active site or metals binding to a different site causing inhibition. Our competitive and non-competitive kinetic assays showed different inhibition profiles. Under competitive conditions Zn2+, Co2+, Mn2+, and Cu2+ can bind to the enzyme active site and lead to inhibition but under non-competitive conditions Zn2+, Co2+, and Mn2+ partially inhibit PHD2 suggesting that these metals cannot displace the Fe2+ from the active site. XAS experiments with Zn2+ and Fe3+ indicate that Zn2+ binds to the surface of PHD2 in a six-coordinate manner composed of two Cys201, 208, His205, Tyr197 and two water ligands.
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Steinhardt, Maximilian Johannes. "Einfluss des Prolyl-4-Hydroxylase-Domäne 2-Enzyms auf die Migration der myeloischen Zelllinien RAW und J774." Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3E11-9.
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Abou, El Nasr Ahmed Abd El Wahed Aly Abou El Nasr. "Use of peptide microarrays for mapping viral b cell epitopes." Doctoral thesis, 2011. http://hdl.handle.net/11858/00-1735-0000-0006-ADF6-4.
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Mount, Kristy Lee Beavers. "The Haemophilus ducreyi SAP Transporter Contributes to Antimicrobial Peptide Resistance." Thesis, 2009. http://hdl.handle.net/1805/1951.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Haemophilus ducreyi is the causative agent of the genital ulcer disease chancroid, which has been shown to facilitate the transmission of HIV. H. ducreyi is likely exposed to multiple sources of antimicrobial peptides in vivo. APs are small, cationic molecules with both bactericidal and immunomodulatory functions. Because H. ducreyi is able to establish and maintain an infection in an environment rich with antimicrobial peptides, we hypothesized that the bacterium was resistant to the bactericidal effects of these peptides. Using a 96-well AP bactericidal assay, we examined H. ducreyi susceptibility to eight human APs likely to be encountered at the site of infection, including the α-defensins human neutrophil peptide-1, human neutrophil peptide-2, human neutrophil peptide-3, and human defensin 5, the β-defensins human β defensin-2, human beta defensin-3, and human beta defensin-4, and the human cathelicidin, LL-37. H. ducreyi survival was compared to the survival of Escherichia coli ML35, a strain known to be susceptible to several antimicrobial peptides. H. ducreyi was significantly more resistant than E. coli ML35 to the bactericidal effects of all peptides tested. Furthermore, we found that representative class I and class II strains of H. ducreyi were each resistant to APs of each functional category, indicating that resistance to antimicrobial peptides could represent a conserved method of pathogenesis for H. ducreyi as a species. The H. ducreyi genome contains a homolog for the Sap influx transporter. To study the role of the H. ducreyi Sap transporter in AP resistance, we generated an isogenic sapA mutant and used the 96-well AP bactericidal assay to compare the AP susceptibility profiles of wild-type H. ducreyi, the sapA mutant and the sapA trans-complement to α-defensins, β-defensins, and LL-37. We observed a 25% decrease in the survival of the sapA mutant when it was exposed to LL-37. These findings suggest that the H. ducreyi Sap transporter plays a role in H. ducreyi resistance to LL-37, but it is likely that other AP resistance mechanisms co-exist within the bacterium.
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"Polar Cap Ionospheric Oscillations in the ULF Frequency Range Observed With SuperDARN HF Radar." Thesis, 2013. http://hdl.handle.net/10388/ETD-2013-08-1149.
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Pc3-4 waves are recorded as geomagnetic pulsations with periods of 6-100s. They are generated at the bowshock and propagate to mid and auroral latitudes as Alfvén waves along closed magnetic field lines. At these latitudes Pc3-4 waves have been studied on the ground using magnetometers and in the ionosphere using HF radar. These waves have also been observed using magnetometers at polar latitudes even though there is no known propagation mechanism to the “open” field lines of the polar cap regions.
In this work we used PolarDARN stations at Rankin Inlet and Inuvik to attempt the first study of Pc3-4 waves in the polar cap regions using radar. In ground scatter data, Doppler velocity oscillations with frequencies in the Pc3-4 range were found to be a common daytime occurrence. The oscillations are spatially coherent and in phase along the beam’s line of sight, matching lower latitude observations. However, upon further study it became apparent that the characteristics of the oscillations are different from those known for Pc3-4 waves.
The observed oscillations have a diurnal trend that shows peaks in activity at 7:00 and 14:00MLT, where Pc3-4 oscillations have a diurnal peak at 10:30-11:00 MLT. In addition, poor coherence was observed between oscillations in radar and ground magnetic field variations at the nearby Taloyoak magnetometer. Further confounding the problem, we found that although the oscillations were coherent along the line-of-sight of the radar, poor coherence is observed when comparing
oscillations in different beams separated by similar spatial scales. This finding counters both the spatial coherence observed along the beam’s line of sight and the spatial coherence of Pc3-4 waves
at auroral latitudes. We conclude that it is unlikely that the observed oscillations are the result of Pc3-4 ULF waves. We instead propose that the observed Doppler velocity oscillations are caused by a change in the ionization along the ray’s path due to auroral particle precipitation.
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Pramanik, Preeti. "Characterization of the FTF/HNF-4 sites within the 7 alpha- and 12 alpha-hydroxylase promoters involved in the bile acid-mediated transcription of their regulation /." 2006. http://hdl.handle.net/10156/1723.
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Παπαθεοδώρου, Χαράλαμπος. "Προγνωστική αξία ανοσοϊστοχημικών μοριακών δεικτών (άξονας SDF1 / CΧCR4) σε πρωτοπαθή καρκινώματα μαστού". Thesis, 2011. http://hdl.handle.net/10889/5666.
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Ο καρκίνος του μαστού αποτελεί τον πιο συχνό τύπο καρκίνου των γυναικών. Παρότι η σχετική έρευνα είναι αρκετά εκτεταμένη, οι υποκείμενοι μηχανισμοί δεν έχουν πλήρως αποσαφηνιστεί. Πρόσφατες μελέτες έχουν αναδείξει τη σημαντικότητα της διαντίδρασης των καρκινικών κυττάρων και του καρκινικού μικροπεριβάλλοντος ως μια κομβική συνιστώσα στη παθοφυσιολογίας της νόσου. Σκοπός της παρούσας μελέτης είναι η διερεύνηση της ανοσοϊστοχημικής έκφραση του υποδοχέα CXCR4, της χημοκίνης SDF-1, της μεταλλοπρωτεϊνάσης MMP-9 και του παράγοντα HIF-1α σε διηθητικά καρκινώματα του μαστού και στον παρακείμενο μη καρκινικό ιστό (τόσο στο επιθηλιακό όσο και στο στρωματικό στοιχείο), καθώς και οι συσχετίσεις των ποικίλων ανοσοεντοπίσεων με τις κλινικοπαθολογοανατομικές παραμέτρους και την επιβίωση. η επιλογή των μορίων έγινε βάσει της σημαντικότητάς τους σε ποικίλα στάδια της παθογένειας της νόσου (υποξία, νεοαγγείωση, ανάπτυξη κτλ). Η έκφραση όλων των υπό εξέταση μορίων ήταν στατιστικά σημαντικότερη στον καρκινικό ιστό σε σχέση με τον παρακείμενο μη νεοπλασματικό. Από τα αποτελέσματα προκύπτει επίσης συσχέτιση μεταξύ ανοσοϊστοχημικών εντοπίσεων της MMP-9 και των υπολοίπων υπό διερεύνηση μορίων. Προέκυψαν επίσης ποικίλες συσχετίσεις μεταξύ συγκεκριμένων προτύπων έκφρασης (pattern) και προγνωστικών παραγόντων. Η έκφραση της MMP-9 στο κυτταρόπλασμα των καρκινικών κυττάρων σχετίστηκε θετικά με τη λεμφαδενική προσβολή, αλλά αρνητικά με το μέγεθος του όγκου. Επίσης, η έκφραση του CXCR4 και της SDF-1 στα καρκινικά κύτταρα σχετίστηκε με την παρουσία οστικών μεταστάσεων και με τον ιστολογικό βαθμό κακοήθειας, αντίστοιχα. Επιπλέον, η ανοσοεντόπιση της SDF-1 στους ινοβλάστες του καρκινικού στρώματος συσχετίστηκε θετικά με την έκφραση του Ki67 και με το στάδιο κατά ΤΝΜ, ενώ η ανοσοεντόπιση της SDF-1 στα ενδοθηλιακά κύτταρα του καρκινικού στρώματος με την έκφραση του Her2. Η ανοσοϊστοχημική έκφραση του HIF-1α συσχετίστηκε αρνητικά με την έκφραση των στεροειδικών υποδοχέων ER και PR. Επιπλέον, η έκφραση της MMP-9 στους ινοβλάστες του καρκινικού στρώματος και η έκφραση της SDF-1 στα επιθηλιακά κύτταρα και στους ινοβλάστες του παρακείμενου μη καρκινικού ιστού συσχετίστηκαν με δυσμενέστερη επιβίωση. Το εύρημα αυτό τονίζει τη σημαντικότητα τόσο του στρώματος όσο και του ξενιστή στην παθογένεια του καρκίνου. Τα αποτελέσματα αυτά αναδεικνύουν τη σημαντικότητα των υπό μελέτη μορίων στην καρκινογένεση και στην εξέλιξη της νόσου. Για την επαλήθευση των αποτελεσμάτων αυτών απαιτείται η διενέργεια μελετών μεγαλύτερης κλίμακας ενώ προσεγγίσεις με λειτουργικές μεθοδολογίες θα μπορούσαν να αναδείξουν πιθανώς κοινά ή διαπλεκόμενα υποκείμενα μηνυματοδοτικά μονοπάτια στα οποία εμπλέκονται τα ως άνω μόρια.<br>Breast cancer is the most frequently diagnosed cancer in women. Despite the ongoing research in breast cancer tumorigenesis the underlying mechanisms are not yet well elucidated. In recent years, the interaction between tumour cells and tumour microenvironment has gained appreciation as an active participant in cancer pathophysiology. In the present study we attempt to investigate the immunohistochemical staining of CXCR4, SDF-1, MMP-9 and HIF-1a in invasive breast cancer and adjacent normal breast tissue (including epithelial and stromal components) and to determine the relationship between different expression patterns and various tumor clinicopathological parameters and survival. The understudy molecules where chosen due to their crucial role in different steps of breast cancer progression (tumor growth, hypoxia, neovascularisation, invasiveness etc). All molecules showed statistically significant higher expression in cancer tissue compared to expression in the adjacent noncancerous tissue. Our results reveal a correlation between expression patterns of MMP9 and the other understudy molecules (SDF1, CXCR4 and HIF-1a). Furthermore, MMP9 expression in fibroblasts of cancer stroma and SDF1 expression in normal epithelial cells and fibroblasts of adjacent normal stroma were associated with poorer survival, underscoring the importance of tumor microenvironment and host derived molecules in tumor progression. There were also various correlations between specific expression patterns and prognostic factors: MMP9 expression in cancer cells was positively correlated with lymph node involvement, but negatively with tumor size,¬ while CXCR4 and SDF-1 expression in cancer cells was positively correlated with bone metastases and tumor grade, respectively. Furthermore, SDF-1 immunoexpression of cancer stromal fibroblasts was positively correlated with Ki67 expression and TNM stage, whereas SDF1 immunoexpression in endothelial cells of cancer stroma was positively correlated with Her2 expression. HIF-1a expression in cancer cells was negatively correlated with expression of steroid receptors. The abovementioned results underline the importance of the understudy molecules in carcinogenesis and tumor progression. Larger scale studies are necessary to confirm our results, while functional approaches could possibly reveal common or interwoven molecular pathways for the understudy molecules.
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Swain, Lija. "Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions." Doctoral thesis, 2014. http://hdl.handle.net/11858/00-1735-0000-0022-5F15-A.
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