MOREHOUSE CCRE DP2- P47PHOX GENETIC POLYMORPHISMS IN CARDIOVASCULAR DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 越来越多的证据表明，氧化应激在血管疾病的发病机制中起着关键作用。超氧化物歧化酶(02-)和过氧化氢(H202)等活性氧物种(ROS)对血管平滑肌细胞(VSMC)的生长和迁移、内皮功能和炎症都有深远的影响。ROS稳态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，是VSMC生长和肥大所必需的。这一建议以NAD(P)H氧化酶的关键调节亚基p47Phox为中心。目前，关于p47Phox基因变异对其基因表达的影响和心血管疾病的发生发展的信息相对较少。为了解决这一问题，我们假设p47Phox基因存在新的遗传变异，可能影响其基因表达或蛋白活性，并易发生心血管疾病。因此，我们提出了以下具体目标：1)建立p47Phox基因座上的高密度遗传变异图和连锁不平衡图；2)表征p47Phox基因变异对NADPH氧化酶活性的功能影响，这是通过从一组血管疾病患者的永生化淋巴母细胞中测量到的，以及对p47Phox启动子研究的经典分析；以及3)在我们合作团队可获得的基于两种族人群的样本中，对p47Phox基因型与氧化应激和血管功能的定量生物标记物进行遗传关联研究。我们期待这个项目将为ROS动态平衡的分子决定因素提供重要的新见解。我们期望这个发展项目将在一个强大的指导和协作团队的指导下，为PI提供一个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.