Role of Epigenetics in the Regulation of Blood Pressure

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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.