Vascular Epigenome Dynamics in African-American Hypertensives

描述（由申请人提供）：高血压是导致美国死亡和残疾的主要原因的最常见的可改变风险因素。它是一种复杂的遗传性疾病，涉及环境因素和多个遗传易感性等位基因之间的相互作用。据推测，非洲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，血管的“记忆”，管理这些慢性变化的分子机制仍然不清楚。我们的中心假设提出，高血压血管疾病的慢性维持和进行性是由血管表观基因组的动态变化介导的，这种动态变化促进了“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，并定义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：“有一个独特的'分子签名'的血管转录组和相应的表观基因组模式的DNA和组蛋白甲基化，这是特征的微血管的非裔美国人与高血压相比，年龄匹配的非裔美国人对照无高血压。“血管紧张素II的药理学阻断在治疗高血压中的临床疗效部分是由其对DNA和组蛋白甲基化的表观基因组模式的独特动态效应及其对血管转录组的影响介导的。“DASH饮食的降血压功效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影响介导的。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，并将遗传学，表观遗传学，营养基因组学和药物基因组学整合到一种常见的临床重要疾病中，这种疾病导致心血管健康的种族/民族差异。预计这些研究将为高血压的治疗提供新的见解和新的药物发现范例。公共卫生相关性：高血压影响美国三分之一的成年人，是中风和心脏病发作的主要原因。它涉及遗传易感性和外部因素之间的相互作用，如饮食（例如高盐摄入量）。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，即促进或保护个体免受高血压的基因的表达受到对饮食营养素变化做出反应的表观遗传标记或代码的调节。

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.