IUGR Affects Renal 11?-HSD2 Epigenetic Characteristics

描述(由申请人提供)：来自我们实验室和其他机构的越来越多的证据表明，成人疾病起源于子宫，很可能通过染色质结构的表观遗传变化(改变的“组蛋白密码”)重新编程基因表达而发生。子宫胎盘功能不全(UPI)是人类发病的一个重要原因，它导致宫内生长受限(IUGR)，并增加严重的肾脏相关成人疾病的风险，如高血压。导致人类高血压的一种机制是11β-羟基类固醇 脱氢酶2型(11？-HSD2)缺乏症。这种酶通过将糖皮质激素代谢成肾脏中不活跃的形式来调节肾脏对类固醇的敏感性。重要的是，在一个具有良好特征的IUGR和成人型高血压动物模型中，我们已经证明了肾脏11？-HSD2水平在幼年期和成年期持续降低。调节肾脏11？-HSD2mRNA水平的机制在很大程度上是未知的，构成了本研究的目标。在这项建议中，我们假设IUGR以基因特异性的方式影响染色质结构的肾脏表观遗传决定因素，导致11？-HSD2表达永久下调。在目标1中，我们将表征IUGR诱导的肾11？-HSD2染色质修饰。在目标2中，我们将确定IUGR如何影响特定转录因子的结合，以及如何导致11？-HSD2表达的变化。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和肾脏11？-HSD2减少的表观遗传学改变。

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.