RGS Protein Function and Regulation

描述（由申请人提供）： 该项目旨在确定RGS蛋白的生理和机制功能，RGS蛋白通过心血管、免疫、神经和感觉系统中的数百种G蛋白偶联受体调节信号传导。目前它专注于RGS 2，P.I.是血压的重要调节器。核心假设是RGS 2部分通过控制控制血管张力的信号通路来调节血压。该假设得到初步数据的支持，这些数据显示：1）RGS 2敲除小鼠为高血压; 2）RGS 2敲除小鼠的动脉显示增强的收缩和不成对的舒张; 3）RGS 2敲除小鼠的血管平滑肌细胞显示增强的血管收缩剂诱导的Ca 2+信号传导和受损的cGMP依赖性蛋白激酶（PKG）的血管舒张信号传导。该项目将确定RGS 2与PKG协同调节信号通路的分子机制，这些信号通路控制阻力动脉血管平滑肌细胞的血管收缩和舒张。通过这样做，该项目将揭示可能在人类高血压中受损的血压调节的新机制原则，这将有助于开发基于机制的诊断和治疗这种知之甚少的疾病。

DESCRIPTION (provided by applicant): This project aims to define the physiologic and mechanistic functions of RGS proteins, which regulate signaling by hundreds of G protein coupled receptors in the cardiovascular, immune, nervous and sensory systems. Currently it focuses on RGS2, which the P.I. has discovered is an important regulator of blood pressure. The central hypothesis is that RGS2 regulates blood pressure in part by controlling signaling pathways governing vascular tone. This hypothesis is supported by preliminary data showing that: 1) RGS2 knockout mice are hypertensive; 2) arteries from RGS2 knockout mice display augmented contraction and unpaired relaxation; 3) vascular smooth muscle cells from RGS2 knockout mice exhibit augmented vasoconstrictor-induced Ca2+ signaling and impaired vasodilatory signaling by cGMP-dependent protein kinase (PKG). This project will determine the molecular mechanisms by which RGS2 in concert with PKG regulates signaling pathways that control vascular contraction and relaxation in vascular smooth muscle cells from resistance arteries. In so doing, this project will reveal new mechanistic principles of blood pressure regulation that may be impaired in human hypertension, which would contribute to development of mechanism-based diagnosis and treatment of this poorly understood disease.