MOREHOUSE CCRE DP2- P47PHOX GENETIC POLYMORPHISMS IN CARDIOVASCULAR DISEASE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。越来越多的证据表明，氧化应激在血管疾病的发病机制中具有关键作用。活性氧（ROS）如超氧化物（O2-）和过氧化氢（H2 O2）对血管平滑肌细胞（VSMC）的生长和迁移、内皮功能和炎症具有深远的影响。ROS体内平衡的失衡与动脉粥样硬化、高血压和肥胖有关。NAD（P）H氧化酶是血管细胞中02-的主要来源并且是VSMC生长和肥大绝对需要的酶。这一建议是集中在p47 phox，一个关键的调节亚基的NAD（P）H氧化酶。目前，关于p47 phox基因变异对其基因表达和心血管疾病发展的影响的信息相对较少。为了解决这个问题，我们假设有新的遗传变异的p47 phox基因，可能会影响其基因表达或蛋白质活性，并容易发展为心血管疾病。因此，我们提出了以下具体目标：1）建立p47 phox基因位点的高密度遗传变异图谱和连锁不平衡图谱; 2）在来自血管疾病患者队列的一组永生化淋巴母细胞中测量p47 phox基因变异对NADPH氧化酶活性的功能影响以及p47 phox启动子研究的经典分析;和3）在作为我们的合作团队的一部分可获得的基于两种族人群的受试者样本中进行p47 phox基因型与氧化应激和血管功能的定量生物标志物的遗传关联研究。我们预计，该项目将提供重要的新的见解的ROS稳态的分子决定因素。我们期望这个发展项目将在强大的指导和合作团队的指导下为PI提供极好的培训和职业机会。

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.