RGS PROTEIN FUNCTION AND REGULATION

描述（由申请人提供）：该项目的长期目标是确定RGS蛋白的功能和调节它们的机制。本申请的焦点是RGS2，其在小鼠和人类中与高血压遗传相关。中心假设是RGS2通过在血管平滑肌、血管内皮和肾脏中执行离散功能来调节血压。该项目的重点是RGS2通过在血管平滑肌、内皮中发挥作用来调节血管收缩和舒张以及调节肾单位中的液体运输的能力。其使用细胞类型特异性RGS2敲除小鼠结合生物化学、细胞生物学、生理学和成像方法来解决以下特定目的：1）确定RGS2降解在血管平滑肌中是如何调节的; 2）确定RGS2在血管平滑肌、内皮和肾单位中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;和4）确定RGS2是否调节血管收缩剂离体和体内调节RhoA信号传导的能力。因此，该项目推进了对高血压的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。 公共卫生相关性：高血压影响着5000万美国人，由于其与心血管疾病、肾衰竭、糖尿病和中风的风险大大增加有关，使这种疾病成为主要的死亡风险因素。高血压造成巨大的临床和社会负担，因为约70%的患者群体通过目前可用的治疗方法治疗效果不佳。当治疗方法可以根据患者的遗传学进行调整时，治疗方法可能会得到改善。该项目通过确定新发现的高血压相关基因RGS2如何调节血压来推进这一目标。

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.