Role of Epigenetics in the Regulation of Blood Pressure

表观遗传学在血压调节中的作用

• 批准号: 7471049
• 负责人: Methode Bacanamwo
• 金额: $ 13.01万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471049
• 关键词: Acetylation; Affect; Angiotensin II; Bacteria; Bioinformatics; Biology; Biomedical Research; Blood Vessels; Candidate Disease Gene; Cardiovascular system; Chronic Disease; CpG methylase; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Data; Disease; Doctor of Philosophy; Endothelial Cells; Epigenetic Process; Event; Family history of; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Grant; Histone Acetylation; Histone Deacetylation; Histone H3; Histones; Human; Hylobates Genus; Hypertension; Illinois; In Vitro; Journals; Lysine; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Messenger RNA; Methylation; Neurodegenerative Disorders; Paper; Pathogenesis; Plant Model; Postdoctoral Fellow; Promoter Regions; Proteins; Publishing; RNA Interference; Rate; Relative (related person); Repression; Research; Research Institute; Role; Secondary Hypertension; Structure; Testing; Therapeutic; Time; Training; Transcriptional Activation; Transcriptional Regulation; Universities; Up-Regulation; Vascular remodeling; Yeasts; blood pressure regulation; cell growth; familial hypertension; gene repression; genome sequencing; improved; inhibitor/antagonist; interest; mRNA Expression; medical schools; novel; prevent; promoter; research study; tool

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.

描述（由申请人提供）： 获得博士学位后，1996年从伊利诺伊大学毕业后，Bacanamwo博士作为博士后研究员使用细菌、酵母和植物模型进行基因表达调控研究。他在一些好的期刊上发表了8篇论文。在他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，并且由于家族史，他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，以追求他对基因表达调控的兴趣，这次是在疾病方面。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（Drs Harrison，Gibbons和Chen）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（Dnmt 1）在收缩性高血压血管重塑中的介导作用”。高血压血管病变与几种慢性疾病如癌症和神经退行性疾病有许多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发病机制中涉及的最重要的表观遗传事件。DNA甲基化介导的基因抑制在高血压血管重构中的作用尚不清楚。我们的初步研究结果表明，在基因和血管紧张素II（Ang II）诱导的高血压血管重塑过程中，DNA甲基转移酶1（Dnmt 1）的表达上调。我们假设高血压血管重塑的发病机制涉及Dnmt 1的激活和DNA甲基化介导的抑制血管重塑基因的抑制剂，如参与血管细胞生长和基质重塑的基因。为了验证这一假设，我们将：目的I：定义Dnmt 1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介导作用。目的II：确定在收缩性血管重构中被Dnmt 1抑制的基因。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，这些研究将提供缩窄性血管重塑的发病机制涉及与Dnmtl介导的基因抑制相关的表观遗传机制的第一证据，并且将开始定义在缩窄性血管重塑中表观遗传下调的基因。这些研究还将确立Dnmtl抑制在治疗缩窄性血管重塑中的治疗潜力，并且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，例如具有几个具有小累加效应的基因的高血压。