Vascular Epigenome Dynamics in African-American Hypertensives

描述(申请人提供)：在美国，高血压是导致死亡和残疾的主要原因的最常见的可改变的危险因素。它是一种复杂的、可遗传的多因素病因疾病，涉及环境因素和多个遗传易感等位基因之间的相互作用。据推测，在非裔美国人中高血压血管疾病的高患病率和更致命的过程反映了由血管表观基因组介导的基因和环境之间的关键相互作用。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，支配这些慢性变化的血管“记忆”的分子机制仍然不清楚。我们的中心假设是，高血压血管疾病的慢性维持和进行性本质是由血管表观基因组的动态变化所介导的，这些动态变化促进了“血管病变”基因表达谱的选择性上调，以及内在“血管保护”基因的协调抑制。拟议的项目将利用全基因组、深度测序技术来表征与高血压血管转录组变化相关的DNA和组蛋白甲基化标记的地形图，并确定血管表观基因组对治疗干预的动态反应。我们将测试几个相关的假设：“与没有高血压的非裔美国人相比，患有高血压的非裔美国人的微血管系统具有独特的‘分子特征’的血管转录组以及相应的DNA和组蛋白甲基化的表观基因组模式。”血管紧张素II的药物阻断治疗高血压的临床疗效部分是通过其对DNA和组蛋白甲基化表观基因组模式的独特的动态效应以及由此对血管转录组的影响而实现的。DASH饮食的降压效果是由血管表观基因组中特定的营养反应元件及其对血管转录组的后续影响所介导的。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，并在一种常见的临床显著疾病中实现遗传学、表观遗传学、营养基因组学和药物基因组学的新整合，这种疾病会导致心血管健康方面的种族/民族差异。预计这些研究将为高血压的治疗带来新的见解和新的药物发现范例。与公共健康相关：在美国，高血压影响着三分之一的成年人，是中风和心脏病发作的主要原因。它涉及遗传易感性与饮食(如高盐摄入量)等外部因素之间的相互作用。调节饮食对血管功能的长期影响的途径尚不清楚。该项目将测试这样一种假设，即促进或保护个人免受高血压影响的基因的表达受到表观遗传标记或密码的调节，这些标记或密码对饮食营养物质的变化做出反应。

DESCRIPTION (provided by applicant): 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. Public Health Relevance: High blood pressure affects 1 in 3 adults in the US and is a major cause of strokes and heart attacks. It involves the interplay between genetic predisposition and external factors such as diet (e.g. high salt intake). The pathways that mediate the long-term effects of diet on the function of the blood vessel are unknown. This project will test the hypothesis that the expression of genes that promote or protect individuals from hypertension is modulated by epigenetic marks or codes that are responsive to changes in dietary nutrients.