RGS Protein Function and Regulation

描述(由申请人提供)： 该项目旨在确定RGS蛋白的生理和机械功能，RGS蛋白通过心血管、免疫、神经和感觉系统中的数百个G蛋白偶联受体调节信号。目前它的重点是RGS2，P.I.已经发现它是一种重要的血压调节因子。中心假说是，RGS2部分通过控制控制血管张力的信号通路来调节血压。这一假说得到以下初步数据的支持：1)RGS2基因敲除小鼠患高血压；2)RGS2基因敲除小鼠的动脉显示出收缩增加和不成对的松弛；3)RGS2基因敲除小鼠的血管平滑肌细胞通过cGMP依赖的蛋白激酶(PKG)介导的血管收缩诱导的钙信号转导增加和血管扩张信号转导受损。该项目将确定RGS2与PKG共同调控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松弛。通过这样做，该项目将揭示人类高血压可能受损的新的血压调节机制原理，这将有助于这种鲜为人知的疾病的基于机制的诊断和治疗的发展。

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.