This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is accumulating evidence that oxidative stress has a critical role in the pathogenesis of vascular disease. Reactive oxygen species (ROS) such as superoxide (02-) and hydrogen peroxide (H202) have profound effects on vascular smooth muscle cell (VSMC) growth and migration, endothelial function and inflammation. An imbalance in ROS homeostasis is associated with atherosclerosis, hypertension, and obesity. NAD(P)H oxidase is an enzyme that is the major source of 02- in vascular cells and absolutely required for VSMC growth and hypertrophy. This proposal is centered on p47phox, a key regulatory subunit of NAD(P)H oxidase. Currently there is relatively little information concerning the impact of p47phox genetic variations on its gene expression and development of cardiovascular disease. To address this issue, we hypothesize that there are novel genetic variants of p47phox gene that may influence its gene expression or protein activity and predispose to development of cardiovascular disease. Accordingly, we propose the following specific aims: 1) establish a high-density genetic variant map and linkage disequilibrium map on the p47phox gene locus; 2) characterize the functional impact of p47phox genetic variants on NADPH oxidase activity as measured in an set of immortalized lymphoblatoid cells from a cohort of patients with vascular disease as well classical analysis of p47phox promoter study; and 3) perform a genetic association study of the p47phox genotype with quantitative biomarkers of oxidative stress and vascular function in a bi-racial population-based sample of subjects that is accessible as part of our collaborative team. We anticipate that this project will provide important new insights into the molecular determinants of ROS homeostasis. It is our expectation that this developmental project will provide an excellent training and career opportunity for the PI under the guidance of a strong mentoring and collaborating team.
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