RGS Protein Function and Regulation

RGS 蛋白功能和调控

• 批准号: 7533445
• 负责人: Kendall J Blumer
• 金额: $ 49.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533445
• 关键词: Address; Affect; Agonist; Alleles; Arteries; Binding; Binding Sites; Biological Assay; Blood Pressure; Blood Vessels; Cardiovascular system; Collection; Cyclic GMP-Dependent Protein Kinases; Data; Defect; Development; Diagnosis; Disease; Exhibits; Fura-2; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; GTPase-Activating Proteins; Genes; Genetic; Human; Hypertension; Image; Immune; In Vitro; Inherited; Kidney; Knock-out; Knockout Mice; Laboratories; Maps; Mediating; Mesenteric Arteries; Methods; Molecular; Mus; Muscle Contraction; Pathway interactions; Phosphorylation; Physiological; Quantitative Trait Loci; RGS Domain; RGS Proteins; RGS2 gene; Reagent; Receptor Gene; Regulation; Relaxation; Research Personnel; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Sympathetic Nervous System; Testing; Vasoconstrictor Agents; Vasodilator Agents; base; blood pressure regulation; dopamine D3 receptor; lifestyle factors; mRNA Expression; mutant; novel; overexpression; pressure; protein function; receptor; research study; response; rho guanine nucleotide exchange factor p115; sensory system

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.

描述（由申请人提供）： 该项目旨在定义RGS蛋白的生理和机械功能，这些功能通过心血管，免疫，神经和感觉系统的数百个G蛋白偶联受体调节信号传导。目前，它侧重于P.I.发现是血压的重要调节剂。中心假设是RGS2通过控制控制血管张力的信号通路来部分调节血压。初步数据表明：1）RGS2基因敲除小鼠具有高血压； 2）RGS2敲除小鼠的动脉表现出增强的收缩和未配对的放松； 3）来自RGS2基因敲除小鼠的血管平滑肌细胞表现出增强血管收缩诱导的Ca2+信号传导和CGMP依赖性蛋白激酶（PKG）的血管舒张信号传导受损。该项目将确定RGS2与PKG结合的分子机制调节信号通路，这些信号通路控制血管平滑肌细胞中的血管收缩和放松，从耐药动脉中。这样一来，该项目将揭示血压调节的新机械原理，这些原理可能会受到人类高血压的损害，这将有助于发展基于机制的诊断和治疗这种知名度知之甚少的疾病。