Vascular Epigenome Dynamics in African-American Hypertensives

非裔美国人高血压的血管表观基因组动力学

• 批准号: 7727216
• 负责人: Gary H Gibbons
• 金额: $ 35万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727216
• 关键词: Adult; Affect; African American; Age; Alleles; Angiotensin II; Blood Vessels; Cardiovascular system; Cause of Death; Characteristics; Chronic; Code; Complex; DASH diet; DNA; DNA mapping; Data; Diet; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Etiology; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Health; High Prevalence; Histones; Hypertension; Hypotension; Indium; Individual; Long-Term Effects; Maintenance; Mediating; Memory; Methylation; Molecular; Molecular Profiling; Myocardial Infarction; Nature; Nutrient; Pathogenesis; Pathway interactions; Pattern; Pharmacogenomics; Repression; Resources; Risk Factors; Stroke; Structure; Technology; Testing; Therapeutic Intervention; Up-Regulation; Vascular Diseases; Virulent; clinical efficacy; clinically significant; disability; drug discovery; epigenomics; genome-wide; hypertension treatment; insight; modifiable risk; novel; public health relevance; racial and ethnic disparities; response; salt intake

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.

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最常见的危险因素。这是一种复杂的，可遗传的多因素病因，涉及环境因素与多个遗传易感性等位基因之间的相互作用。据推测，非裔美国人的高血压血管疾病的高流行和更具毒性的进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。高血压诱导的血管并发症（例如中风）的发病机理涉及血管功能和结构的长期变化。但是，控制这些慢性变化的血管“记忆”的分子机制仍然很差。我们的中心假设是高血压中血管疾病的慢性维持和渐进性是由血管遗传学组的动态变化介导的，这些变化促进了“血管性”基因表达谱的选择性上调，以及对内在的“血管抑制” Vasculo Expection“基因”基因的均匀抑制。拟议的项目将利用全基因组的深层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，并定义了血管表观基因组对治疗干预措施的动态反应。我们将检验几种相关的假设：“血管转录组有独特的“分子特征”，DNA和组蛋白甲基化的相应表观遗传学模式是非裔美国人与高血压相比，非洲裔美国人对临床治疗的临床治疗率相比。部分是由其对DNA和组蛋白甲基化表观基因组模式的独特动态影响及其对血管转录组的影响。 “仪表式饮食的血压降低功效是由血管遗传组中特定的营养响应元素介导的，其随后对血管转录组的影响。总体而言，该项目有望建立独特的表观基因质数据资源和遗传学，表观遗传学，营养和药物的新颖疾病的新颖融合，以促进遗传学，营养和药物的新颖性，这是一种常见的临床，以实现临床范围，这是一种常见的，这是一种常见的，常见的疾病，是一种常见的，在这种疾病中的疾病，在这种疾病中的疾病，在这种疾病中的疾病，共同疾病，是一种常见的疾病，这些疾病是普遍的，在这种疾病中，有希望在心血管健康中，这些研究将产生新的见解和新的药物发现范式，以治疗高血压。该项目未知。