IUGR Affects Renal 11?-HSD2 Epigenetic Characteristics

IUGR 影响肾 11?-HSD2 表观遗传特征

• 批准号: 7666032
• 负责人: Mariana Baserga
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666032
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Adolescent; Adult; Affect; Aldosterone; Animal Model; Bilateral; Binding; Binding Sites; Cell Culture Techniques; Characteristics; Chromatin; Chromatin Structure; Complex; Control Animal; Corticosterone; DNA; DNA Methylation; Data; Dinucleosome; Disease; Down-Regulation; Environment; Enzymes; Epigenetic Process; Exons; Fetal Growth Retardation; Future; Gene Expression; Genes; Genetic Transcription; Glucocorticoids; Goals; Harvest; Histone Code; Histones; Human; Hypertension; Intervention; Investigation; Kidney; Laboratories; Lead; Life; Ligation; Literature; Maps; Messenger RNA; Methylation; Modification; Molecular; Morbidity - disease rate; Oligonucleotides; Pattern; Perinatal; Phenotype; Play; Pregnancy; Proteins; Rattus; Research; Risk; Role; SP1 gene; Sp1 Transcription Factor; Sp3 Transcription Factor; Sprague-Dawley Rats; Staging; Steroids; Structure; Testing; Tissues; Transcriptional Regulation; base; bisulfite; chromatin immunoprecipitation; chromatin modification; in utero; mortality; nephrogenesis; offspring; postnatal; prenatal; programs; promoter; three dimensional structure; transcription factor

DESCRIPTION (provided by applicant): Accumulating evidence from our laboratory and others suggests that adult diseases originate in utero, and likely occur through the reprogramming of gene expression via epigenetic changes in chromatin structure (altered "histone code").Uteroplacental insufficiency (UPI) is a significant cause of morbidity in humans that leads to intrauterine growth restriction (IUGR) and increases the risk of serious kidney related adult morbidities, such as hypertension. One mechanism that can lead to hypertension in humans is 11 beta-hydroxysteroid dehydrogenase type 2 (11¿-HSD2) deficiency. This enzyme regulates renal steroid sensitivity by metabolizing glucocorticoids to an inactive form in the kidney. Importantly, in a well characterized animal model of IUGR and adult onset hypertension, we have demonstrated persistent decreased levels of kidney 11¿-HSD2 levels through juvenile and adult stages. The mechanisms that regulate kidney 11¿-HSD2 mRNA levels are largely unknown and constitute the target of the present investigation. In this proposal we hypothesize that IUGR affects kidney epigenetic determinants of chromatin structure in a gene-specific manner resulting in permanent down regulation of 11¿-HSD2 expression. In Aim 1 we will characterize IUGR- induced chromatin modifications of renal 11¿-HSD2. In Aim 2, we will determine how the binding of specific transcription factors can be affected by IUGR and can result in altered expression of 11¿-HSD2. Ultimately, these studies will provide a basis for potential dietary and/or specific pharmacological interventions that can reverse or moderate the epigenetic alterations underlying decreased kidney 11¿-HSD2.

描述（申请人提供）：从我们的实验室和其他实验室积累的证据表明，成人疾病起源于子宫内，并且可能通过染色质结构中的表观遗传学变化通过基因表达的重编程而发生（改变的“组蛋白编码”）。子宫胎盘功能不全（UPI）是人类发病的重要原因，导致宫内生长受限（IUGR）并增加严重的肾脏相关成人疾病如高血压的风险。导致人类高血压的一种机制是11 β-羟基类固醇 脱氢酶2型（11 <$-HSD 2）缺乏。这种酶通过将糖皮质激素代谢为肾脏中的非活性形式来调节肾脏类固醇敏感性。重要的是，在IUGR和成人发病高血压的良好表征的动物模型中，我们已经证明了在幼年和成年阶段肾脏11 <$-HSD 2水平的持续降低。调节肾脏11 <$-HSD 2 mRNA水平的机制在很大程度上是未知的，构成了本研究的目标。在这个建议中，我们假设IUGR以基因特异性方式影响染色质结构的肾脏表观遗传决定因素，导致11 <$-HSD 2表达永久下调。在目标1中，我们将描述IUGR诱导的肾11 <$-HSD 2染色质修饰。在目标2中，我们将确定特定转录因子的结合如何受到IUGR的影响，并导致11 <$-HSD 2表达的改变。最终，这些研究将为潜在的饮食和/或特定的药物干预提供基础，这些干预可以逆转或缓解肾脏11-HSD 2减少的表观遗传学改变。