Disparities in Hypertension Risk Amongst Young Adults: The Role of Epigenetics

项目总结/摘要 年轻的非洲裔美国人（AAs）患中风的可能性是欧洲裔美国人的3倍 （EA）。减少年轻AA中卒中差异的一个主要挑战是对以下方面的了解不足： 促进健康无症状AA早发性高血压的分子机制。长期 候选人的目标是建立一个独立的研究生涯，重点是了解社会的作用， 表观基因组学在脑血管疾病中调节种族差异的结果。的目的 应用是系统地研究与异常动脉相关的社会表观基因组机制， 在无症状的黑人与白人中，僵硬模式先于高血压的发展。给定 我们的中心假设是，已知不良经历会介导脉管系统的表观遗传变化， 1）心理社会压力与AA和EA之间cfPWV的差异相关，2） 改变表达的细胞外基质特异性miRNA与cfPWV相关， 心理社会压力。针对这些相互关联的假设，有三个具体目标。目标1（培训-第一阶段） 我们将确定AA和EA学院的心理社会压力和动脉僵硬度之间的关系 学生在这里，我们将通过颈动脉-股动脉脉搏波速度测量的动脉硬度与 使用经验证的调查工具对儿童和成年早期的社会心理压力进行调查。目标2（过渡到 独立，I/II期），我们将确定细胞外基质相关血浆的表达模式， Aim 1中使用从大学生中获得的液体活检样品对AA和EA受试者的血清蛋白进行了研究。我们 将使用ELISA和Western印迹分析评估蛋白质水平。在目标3（独立目标/第二阶段）中，我们将 使用生物信息学方法鉴定细胞外基质的细胞外囊泡和血浆浓度- 相关的microRNA在AA和EA研究对象。在成功完成拟议的研究和 培训，我们希望提供深入了解分子机制，驱动过早的大动脉硬化， 年轻健康的AA种族个体预计这一贡献将非常重要，因为它将提供 延迟AA高血压发作的潜在新治疗途径，有助于缓解 中风发病率和死亡率的差异。我们的研究是创新的，因为它试图改变这种范式， 侧重于有害环境暴露（如虐待、种族主义）的生物嵌入如何影响 过早的大动脉僵硬和相关表观遗传生物标志物的差异表达， microRNAs。此外，它利用跨学科的方法来解决临床问题。拟议 研究将为Buie博士提供一个平台，以获得临床试验设计、实施 和分析此外，她将精通混合方法（定量和定性）研究， 采用生物信息学和表观基因组学原理来解决中风中的健康差异。

Project Summary/Abstract Young African Americans (AAs) are 3X as likely to have a stroke compared to European Americans (EAs). A major challenge for reducing disparities in stroke amongst young AAs is the poor understanding of molecular mechanisms that facilitate early onset hypertension in healthy, asymptomatic AAs. The long-term goal of the candidate is to establish an independent research career focused on understanding the role of social epigenomics in modulating racially disparate outcomes in cerebrovascular diseases. The objective of this application is to systematically investigate social epigenomic mechanisms associated with aberrant arterial stiffness patterns, which precedes the development of hypertension, in asymptomatic blacks vs whites. Given that adverse experiences are known to mediate epigenetic changes in the vasculature, our central hypotheses are that 1) psychosocial stress is associated with differences in cfPWV between AAs and EAs and that 2) altered expression extracellular matrix-specific miRNAs are associated with cfPWV as a function of differences in psychosocial stress. Three specific aims address these interrelated hypotheses. In Aim 1 (Training-Phase I) we will determine the association between psychosocial stress and arterial stiffness in AA and EA college students. Here, we will correlate arterial stiffness, as measured by carotid-femoral pulse wave velocity with childhood and early adulthood psychosocial stress using validated survey tools. In Aim 2 (Transition to Independence, Phase I/II) we will determine the expression patterns of extracellular matrix-relevant plasma and serum proteins in AA and EA subjects using liquid biopsy samples acquired from college students in Aim 1. We will assess protein levels using ELISA and Western blot assays. In Aim 3 (Independent Aim/Phase II) we will use a bioinformatics approach to identify extracellular vesicle and plasma concentrations of extracellular matrix- relevant microRNAs in AAs and EAs study subjects. Upon successful completion of the proposed research and training, we expect to provide insight on molecular mechanisms that drive premature large artery stiffening in young, healthy AAs race individuals. This contribution is expected to be significant because it will provide potential novel therapeutic avenues for the postponement of hypertension onset in AAs that will help alleviate disparities in stroke incidence and mortality. Our research is innovative in that it seeks to shift this paradigm by focusing on the how the biological embedding of adverse environmental exposures (e.g. abuse, racism) impacts premature large artery stiffness and differential expression of relevant epigenetic biomarkers such as microRNAs. Moreover, it utilizes a transdisciplinary approach to address the clinical problem. The proposed studies will provide a platform for Dr. Buie to gain expertise and training in clinical trial design, implementation and analysis. Moreover, she will become proficient in mixed methods (quantitative and qualitative) research and employing bioinformatic and epigenomic principles for addressing health disparities in stroke.