RGS PROTEIN FUNCTION AND REGULATION

项目描述（由申请人提供）：该项目的长期目标是确定RGS蛋白的功能及其调控机制。目前应用的重点是RGS2，它在小鼠和人类中与高血压有遗传联系。核心假设是RGS2通过在血管平滑肌、血管内皮和肾脏中发挥离散功能来调节血压。本项目主要研究RGS2通过在血管平滑肌、内皮中的功能调节血管收缩和舒张的能力，以及在肾单位中调节液体运输的能力。该研究利用细胞类型特异性RGS2敲除小鼠，结合生物化学、细胞生物学、生理学和影像学方法，实现以下具体目标：1)确定血管平滑肌中RGS2降解的调控机制；2)确定血管平滑肌、内皮和肾细胞中RGS2在血压控制中的相对贡献；3)确定RGS2如何促进内皮依赖性血管舒张；4)确定RGS2是否调节血管收缩剂在体内和体外调节RhoA信号的能力。因此，该项目促进了对高血压血压控制机制及其失调的理解，这可能有助于确定新的高血压治疗方法。

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify functions of RGS proteins and the mechanisms that regulate them. The focus of the present application is RGS2, which has been linked genetically in mice and humans to hypertension. The central hypothesis is that RGS2 regulates blood pressure by carrying out discrete functions in vascular smooth muscle, vascular endothelium, and kidney. This project focuses on the ability of RGS2 to regulate vascular contraction and relaxation by functioning in vascular smooth muscle, endothelium and to regulate fluid transport in renal nephron. It uses cell type- specific RGS2 knockout mice in conjunction with biochemical, cell biological, physiological and imaging methods to address the following Specific Aims: 1) determine how RGS2 degradation is regulated in vascular smooth muscle; 2) determine the relative contributions of RGS2 in vascular smooth muscle, endothelium and nephron in blood pressure control; 3) determine how RGS2 promotes endothelium-dependent vascular relaxation; and 4) determine whether RGS2 regulates the ability of vasoconstrictors to regulate RhoA signaling ex vivo and in vivo. Accordingly, this project advances understanding of blood pressure control mechanisms and their dysregulation in hypertension, which may contribute to the identification of new hypertension therapies. PUBLIC HEALTH RELEVANCE: Hypertension affects 50 million Americans, making this condition a leading mortality risk factor due to its association with greatly increased risk of cardiovascular disease, renal failure, diabetes and stroke. Hypertension causes enormous clinical and societal burden because ~70% of the patient population is poorly treated by currently available therapeutics. Improved treatment is likely to occur when therapeutics can be tailored to a patient's genetics. This project advances this goal by determining how a newly identified hypertension-linked gene---RGS2-regulates blood pressure.