Vascular Epigenome Dynamics in African-American Hypertensives

高血压是最常见的可改变的危险因素，导致主要原因 死亡和残疾在美国。它是一种复杂的遗传性疾病， 病因学涉及环境因素和多种 遗传易感等位基因据推测，高流行率和更致命的 非裔美国人高血压血管疾病的病程反映了一个关键的 基因和环境之间的相互作用是由血管表观基因组介导的。 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 控制这些慢性变化的血管“记忆”机制仍然很差 定义了我们的中心假设提出，慢性维持和渐进性 高血压中血管疾病的性质是由高血压中血管内皮细胞的动态变化介导的。 促进“血管病”基因选择性上调的血管表观基因组 表达谱以及内在的“血管保护”的协调抑制 基因.拟议的项目将利用全基因组深度测序技术， 表征与以下相关的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： “血管转录组有一个独特的'分子特征'， 相应的DNA和组蛋白甲基化的表观基因组模式， 非裔美国人高血压患者微血管特征 与无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的药理学阻断在治疗 高血压部分是通过其对表观基因组的独特的动态作用介导的。 DNA和组蛋白甲基化模式及其对血管内皮细胞的影响 转录组 “DASH饮食的降血压功效是由特定的， 维管表观基因组中的营养反应元件及其后续效应 在血管转录组上 总的来说，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型整合， 一种常见的、临床上显著的疾病，导致种族/民族差异， 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例。

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.