Role of Epigenetics in the Regulation of Blood Pressure

描述(由申请人提供)： 1996年在伊利诺伊大学获得博士学位后，巴卡纳姆沃博士以博士后身份利用细菌、酵母和植物模型进行了基因表达调控方面的研究。他在体面的期刊上发表了8篇论文。在意识到人类基因组序列的潜力后，他对生物医学研究产生了兴趣，并由于家族病史而对心血管研究特别感兴趣。他于2001年12月加入莫尔豪斯医学院心血管研究所，追求对基因表达调控的兴趣，这一次是在疾病方面。他的研究兴趣是表观遗传学在血管基因转录调控中的作用。他正在申请培训补助金，以提高他在血管生物学和表观遗传学研究的最新工具方面的培训。他有一个由血管生物学(哈里森、吉本斯和陈博士)以及基因组学和生物信息学工具的领导者组成的指导团队，以研究表观遗传学和基因转录调控。在这项资助中，他想研究“DNA甲基转移酶1(DNMT1)在缩窄性高血压血管重塑中的中介作用”。高血压血管病变与癌症和神经退行性疾病等慢性疾病具有许多共同的遗传和环境触发因素，其中DNA甲基化介导的保护基因沉默似乎是参与发病机制的最重要的表观遗传学事件。目前对DNA甲基化介导的抑制高血压血管重塑基因的作用知之甚少。我们的初步发现证明，在遗传性和血管紧张素II(Ang II)诱导的高血压血管重塑过程中，DNA甲基转移酶1(DNMT1)的表达上调。我们假设高血压血管重塑的发病机制涉及Dnmt1的激活和DNA甲基化介导的血管重塑基因抑制物的抑制，如参与血管细胞生长和基质重塑的基因。为了验证这一假说，我们将：目的1：确定Dnmt1在遗传性高血压和继发性高血压引起的血管结构改变中的中介作用。目的II：确定DNMT1在缩窄性血管重塑中的抑制基因。目的III：明确高血压血管重构候选基因的表达和表观遗传学变化。总之，这些研究将提供第一个证据，表明缩窄性血管重塑的发病机制涉及与Dnmt1介导的基因抑制相关的表观遗传学机制，并将开始定义在缩窄性血管重塑中表观基因下调的基因。这些研究还将确定DNMTL抑制在治疗缩窄性血管重塑中的治疗潜力，这些同时影响几个基因的新疗法特别适合于治疗多基因疾病，如高血压，其中几个基因具有较小的相加效应。

DESCRIPTION (provided by applicant): After getting his Ph.D. in 1996 from the University of Illinois, Dr. Bacanamwo conducted research in gene expression regulation using bacteria, yeast, and plant models as a postdoctoral fellow. He published 8 papers in decent journals. He became interested in biomedical research after he realized the potential with the availability of the human genome sequence and was particularly interested in cardiovascular research due to family history. He joined the Cardiovascular Research Institute at the Morehouse School of Medicine in December 2001 to pursue his interest in gene expression regulation, this time in disease. His research interest is in the role of epigenetics in the transcriptional regulation of vascular genes. He is applying for a training grant to improve his training in vascular biology and the latest tools of epigentics study. He has a mentoring team made of leaders in vascular biology (Drs Harrison, Gibbons, and Chen) and in genomics and bioinformatics tools to study epigenetics and gene transcription regulation. In this grant, he wants to study the "Mediator Role of DNA Methyltransferase 1 (Dnmt1) in Constrictive Hypertensive Vascular Remodeling". Hypertensive vasculopathy shares many of the genetic and environmental triggers with several chronic diseases such as cancer and neurodegenerative diseases where DNA methylation-mediated silencing of protective genes appears to be the most important epigenetic event involved in the pathogenesis. Little is known about the role of DNA methylation-mediated repression of genes that prevent the hypertensive vascular remodeling. Our preliminary findings document an up-regulation in expression of DNA methyltransferase 1 (Dnmt1) during genetic- and angiotensin II (Ang ll)-induced hypertensive vascular remodeling. We hypothesize that the pathogenesis of hypertensive vascular remodeling involves the activation of Dnmt1 and DNA methylation-mediated repression of inhibitors of vascular remodeling genes such as genes involved in vascular cell growth and matrix remodeling. To test the hypothesis, we will: Aim I: Define the mediator role of Dnmt1 in genetic hypertension- and secondary hypertension-induced alteration in vessel structure. Aim II: Determine genes that are repressed by Dnmt1 in constrictive vascular remodeling. Aim III: Define expression and epigenetic changes in candidate genes in hypertensive vascular remodeling. Overall, these studies will provide the first evidence that the pathogenesis of constrictive vascular remodeling involves epigenetic mechanisms related to Dnmtl-mediated gene repression and will begin to define genes that are epigenetically down-regulated in constrictive vascular remodeling. These studies will also establish the therapeutic potential of Dnmtl inhibition in the treatment of constrictive vascular remodeling, and these novel therapies affecting several genes at once are particularly suitable to the treatment of polygenic diseases such as hypertension with several genes having small additive effects.