This proposal entails a three-year training program focused on preparing the applicant for an independent career in academic cardiovascular medicine. This project aims to impart the skills and knowledge required for the applicant to achieve his long-term goal of contributing insights into the genetic underpinnings of heritable vascular disease. The immediate training objectives of the applicant are to master critical experimental techniques, perform coursework that will expand his understanding of advanced molecular biology, develop administrative skills required to function autonomously, and compose a body of work that will enable funding as an independent investigator. Under the guidance of his mentor, Tom Quertermous, and his carefully selected panel of Advisory Committee of senior investigators at Stanford University, the applicant will have the resources and support to achieve these goals and transition to independence. Project Description: Genome-wide association (GWA) studies have recently identified a non-coding region of chromosome 9p21 as the most important source of heritable risk for cardiovascular disease. Independent of traditional risk factors such as smoking, hypertension and hyperlipidemia, the most predictive 9p21 variants account for as much as 21% of the attributable risk for coronary and peripheral vascular disease. Despite being implicated in the leading cause of death in the Western world, the mechanism by which these polymorphisms lead to vascular disease unfortunately remains a mystery. In this proposal, the investigators seek to elucidate the relationship between the intergenic risk-associated region of 9p21 and abdominal aortic aneurysm (AAA) disease. Proposed experiments will build on preliminary work which has implicated the cell- cycle regulatory gene, CDKN2B, as the causative gene responsible for clinical disease. This gene controls several aspects of cell-fate decision making and is highly downregulated in carriers of the risk-allele. On the other hand, its activity in the vasculature remains unknown.
Specific aims to be investigated in this proposal will include: (1) Characterizing the in vivo effects of CDKN2B on AAA formation and blood vessel degeneration (in the mouse elastase model);and (2) Determining the role of CDKN2B in smooth muscle cell apoptosis and inflammation, in vitro. These studies are intended to form the foundation of a lifelong career in cardiovascular genetics and vascular biology for the applicant. Discoveries made in the course of this proposal are intended to support the stated mission of the National Institutes of Health and provide contributions that will lead to the development of new therapies for patients with cardiovascular disease.
Relevance: Scientists do not yet understand how genetic variation causes cardiovascular disease. Recent studies have identified chromosome 9 and the cell-regulating gene, CDKN2B, as possible sources of inherited risk for disease. Understanding how these pathways function might lead to new therapies for heart and blood vessel disorders- currently the leading killers in the United States.
|Kojima, Yoko; Downing, Kelly; Kundu, Ramendra et al. (2014) Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis. J Clin Invest 124:1083-97|
|Downing, Kelly P; Nead, Kevin T; Kojima, Yoko et al. (2014) The combination of 9p21.3 genotype and biomarker profile improves a peripheral artery disease risk prediction model. Vasc Med 19:3-8|
|Leeper, Nicholas J; Raiesdana, Azad; Kojima, Yoko et al. (2013) Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation. Arterioscler Thromb Vasc Biol 33:e1-e10|
|Nead, Kevin T; Cooke, John P; Olin, Jeffrey W et al. (2013) Alternative ankle-brachial index method identifies additional at-risk individuals. J Am Coll Cardiol 62:553-9|
|Leeper, Nicholas J; Myers, Jonathan; Zhou, Margaret et al. (2013) Exercise capacity is the strongest predictor of mortality in patients with peripheral arterial disease. J Vasc Surg 57:728-33|