Molecular Mechanisms of Vascular Relaxation

描述(由申请人提供)： 许多心血管疾病的特点是血管功能紊乱。血管平滑肌细胞(VSMC)张力异常在高血压和动脉粥样硬化的发病机制中起重要作用，但目前尚不清楚。该PPG的长期目标是了解在健康和疾病中调节血管张力的复杂的潜在分子机制。将要检验的基本假设是，调节血管平滑肌细胞收缩和松弛的关键蛋白质的正常功能丧失，直接导致血管运动异常和血压调节紊乱。我们建议的计划利用了广泛和完善的基础设施，以及塔夫茨-新英格兰医学中心分子心脏病研究所(MCRI)、其缺血性心脏病NHLBI SCOR、Framingham心脏研究和麻省理工学院豪斯曼基因组实验室之间的持续合作。提出了四个项目：P1：“血管松弛和心血管反应的遗传学”；P2：“PKG介导的血管松弛机制”；P3：“PKG在血管平滑肌中对BKCa通道的调节”；以及P4：“血管功能障碍作为高血压的病因”。还提出了三个核心(基因组学；鼠标；管理)。我们发现的VSMC蛋白包括三种对正常血压至关重要的蛋白：RGS2，GQ蛋白信号的调节者；雌激素受体a；BKCa钾通道(a和a亚基)，以及两个生理上最相关的肌球蛋白磷酸酶调节激酶，Rho Kinase(ROCK)和PKGIa，一氧化氮/cGMO的效应者。PKGI、RGS2、ERA和BKCa通道基因改变的小鼠都表现出血管收缩异常和高血压。该PPG提供了广泛的初步数据，这些数据来自人类基因组研究、完整的小鼠、小鼠血管环、培养的人和小鼠血管细胞、膜片钳、信号转导实验和详细的肾脏生理学。在整个提案中，聚集的调查人员有效合作的能力得到了证明。有待检验的假设的一个重要推论是，高血压可以由调节血管松弛的VSMC蛋白的初级异常引起。为了正式验证这一假设，将这些关键的VSMC调控基因中的靶向突变引入老鼠体内，并在人类身上寻找。对这种PPG的高度集成研究可能会导致高血压和相关心血管疾病的新诊断和治疗方法。

DESCRIPTION (provided by applicant): Many cardiovascular diseases are characterized by disordered vascular function. Abnormalities in vascular smooth muscle cell (VSMC) tone are important in the pathogenesis of hypertension and atherosclerosis, but are not well understood. The long-term objective of this PPG is to understand the complex underlying molecular mechanisms that regulate vascular tone in health and disease. The fundamental hypothesis that will be tested is that loss of the normal function of the critical proteins that regulate vascular smooth muscle cell contraction and relaxation directly causes abnormal vasomotion and disorders of blood pressure regulation. The program we propose takes advantage of an extensive and well-developed infrastructure and ongoing collaborations between the Tufts-New England Medical Center Molecular Cardiology research Institute (MCRI), its NHLBI SCOR in Ischemic Heart Disease, the Framingham Heart Study, and the Housman Genomics Laboratory at MIT. Four projects are proposed: P1: "Genetics of Vasorelaxation and Cardiovascular Responses"; P2: "Mechanisms of PKG-mediated Vascular Relaxation"; P3: "BKca Channel Regulation by PKG in Vascular Smooth Muscle"; and P4: "Vascular Dysfunction as an Etiology of Hypertension" in Mouse Models. Three Cores are also proposed (Genomics; Mouse; Administrative). The VSMC proteins that are the specific focus of this proposal include three proteins that we show are essential for normal blood pressure: RGS2, the regulator of Gq-protein signaling; estrogen receptor a; and the BKca potassium channel (a and a subunits), as well as the two physiologically most relevant myosin phosphatase regulatory kinases, Rho Kinase (ROCK) and PKGIa, the effector of nitric oxide/cGMO. Genetically altered mice for PKGI, RGS2, ERa and the BKca channel all demonstrate vascular contractile abnormalities and hypertension. This PPG provides extensive preliminary data from human genomic studies, intact mice, mouse vascular rings, cultured human and mouse vascular cells, patch-clamping, signal transduction experiments, and detailed renal physiology. The ability of the assembled investigators to collaborate effectively is demonstrated throughout the proposal. An important corollary of the hypothesis to be tested is the concept that hypertension can arise from primary abnormalities of the VSMC proteins that regulate vascular relaxation. To formally test this hypothesis, targeted mutations in these critical VSMC regulatory genes are introduced into mice and sought in humans. The highly integrated studies of this PPG are likely to lead to new diagnostic and therapeutic approaches to hypertension and related cardiovascular diseases.