Vascular Epigenome Dynamics in African-American Hypertensives

高血压是导致主要原因的最常见的可改变的危险因素 在美国的死亡和残疾。它是一种复杂的、可遗传的多因素疾病。 涉及环境因素和多种疾病之间相互作用的病因学 遗传易感等位基因。据推测，高流行率和更高的毒力 非裔美国人中高血压血管疾病的病程反映了一个关键的 由血管表观基因组介导的基因和环境之间的相互作用。 高血压引起的血管并发症(如中风)的发病机制 涉及血管功能和结构的长期变化。然而，分子 管理这些慢性变化的血管“记忆”机制仍然很差。 已定义。我们的中心假设是慢性维持性和渐进性 高血压血管病变的本质是通过血管紧张素转换酶的动态变化来调节的 促进“血管病变”基因选择性上调的血管表观基因组 内源性“血管保护”基因的表达谱及协同抑制 基因。拟议的项目将利用全基因组、深度测序技术来 描述DNA和组蛋白甲基化标记的地形图 高血压血管转录组的变化以及定义动态 血管表观基因组对治疗干预的反应。我们将测试几个 相关假设： “有一个独特的‘分子标记’的血管转录组和一个 相应的DNA表观基因组模式和组蛋白甲基化，即 非裔美国人高血压患者的微血管特征 与没有高血压的年龄匹配的非裔美国人对照组相比。 血管紧张素II的药物阻断治疗高血压病的临床疗效 高血压在一定程度上是由其对表观基因组的独特的、动态的影响所介导的 DNA和组蛋白甲基化模式及其对血管的影响 转录组。 DASH饮食的降血压功效是通过特定的、 维管表观基因组中的营养响应元件及其后续效应 在血管转录组上。 总体而言，该项目有望创建一个独特的表观基因组数据资源 以及遗传学、表观遗传学、营养基因组学和药物基因组学的新集成 一种常见的、临床上意义重大的疾病，它导致了 心血管健康。预计这些研究将产生新的见解和新的 治疗高血压的药物发现范式。

Hypertension is the most common modifiable risk factor that leads to the major causes of death and disability in the US. It is a complex, heritable disease of multi-factorial etiology that involves the interactions between environmental factors and multiple genetic susceptibility alleles. It is postulated that the high prevalence and more virulent course of hypertensive vascular disease among African-Americans reflects a critical interplay between genes and environment that is mediated by the vascular epigenome. The pathogenesis of hypertension-induced vascular complications (e.g. stroke) involves long-term changes in vessel function and structure. However, the molecular mechanisms of vascular 'memory' that govern these chronic changes remain poorly defined. Our central hypothesis poses that the chronic maintenance and progressive nature of vascular disease in hypertension is mediated by dynamic changes in the vascular epigenome that promote the selective up-regulation of a "vasculopathic" gene expression profile as well as the coordinate repression of intrinsic "vasculo-protective" genes. The proposed project will utilize genome-wide, deep sequencing technology to characterize a topographical map of DNA and histone methylation marks associated with changes in the hypertensive vascular transcriptome as well as define the dynamic response of the vascular epigenome to therapeutic interventions. We will test several related hypotheses: " There is a distinctive 'molecular signature' of the vascular transcriptome and a corresponding epigenomic pattern of DNA and histone methylation that is characteristic of the microvasculature of African-Americans with hypertension compared to age-matched African-American controls without hypertension. " The clinical efficacy of pharmacologic blockade of angiotensin II in the treatment of hypertension is mediated in part by its distinctive, dynamic effects on the epigenomic pattern of DNA and histone methylation and its consequent influence on the vascular transcriptome. " The blood pressure lowering efficacy of the DASH diet is mediated by specific, nutrient-responsive elements in the vascular epigenome and its consequent effects on the vascular transcriptome. Overall, this project holds promise for creating a unique Epigenomic Data Resource and a novel integration of genetics, epigenetic, nutrigenomics and pharmacogenomics in a common, clinically significant disease that contributes to racial/ethnic disparities in cardiovascular health. It is anticipated that these studies will yield novel insights and new drug discovery paradigms for the treatment of hypertension.