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In Vivo Mechanisms of Integrated G protein Signaling Regulation by RGS Proteins

RGS 蛋白整合 G 蛋白信号传导调节的体内机制

基本信息

批准号：
10077581
负责人：
Patrick Osei-Owusu
金额：
$ 40.25万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077581
关键词：
Ablation Acetates Acute Address Anesthesia procedures Angiotensin II Biochemistry Biological Biological Assay Blood Pressure Blood Vessels Bradykinin Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Cell Death Cessation of life Chronic Conscious Cyclic AMP Defect Deoxycorticosterone Disease Dosage Compensation (Genetics)Echocardiography Endothelin-1 Etiology Functional disorder Fura-2 G-Protein Signaling Pathway G-Protein-Coupled Receptors GTP-Binding Protein Regulators GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins GTPase-Activating Proteins Gene Dosage Generations Genes Goals Guanosine Triphosphate Heart Heart Diseases Heart Hypertrophy Heart Rate Heart failure Histology Homeostasis Hydrolysis Hypertension Hypertrophic Cardiomyopathy Hypertrophy Image In Vitro Infusion procedures Knockout Mice Knowledge Mediating Mesenteric Arteries Molecular Molecular and Cellular Biology Monitor Mus Muscle Cells Myocardial Norepinephrine Operative Surgical Procedures Organ Outcome Study Pathologic Pathway interactions Pharmaceutical Preparations Phenotype Phenylephrine Phosphorylation Physiological Physiology Predisposition Process Proteins RGS Proteins RGS2 gene Regulation Renal Blood Flow Renal function Signal Pathway Signal Transduction Signaling Protein Sodium Chloride Stress Structure System Testing Therapeutic Time Vascular Smooth Muscle Vasoconstrictor Agents Western Blotting Work autocrine biological systems blood pressure regulation body system dietary effective therapy femoral artery heart function in vivo insight male member mortality mouse model novel paracrine pressure protein function relating to nervous system response tool

项目摘要

Title: In Vivo Mechanisms of Integrated G protein Signaling Regulation by RGS Proteins Project Abstract G protein signaling is involved in the function of many biological systems including neural, humoral, autocrine, and paracrine systems that maintain physiological homeostasis. Defects that result in increased G protein signaling have been implicated in many pathophysiological disorders, most notably hypertension and heart disease. Therefore, efforts that increase the understanding of G protein regulation are a major approach to understand disease etiology and develop more effective treatments for cardiovascular disorders. Regulators of G protein signaling (RGS) regulate G protein signaling by acting as GTPase-activating proteins (GAPs), accelerating GTP hydrolysis to terminate G protein activity. Many RGS proteins, including all members of the R4/B subfamily, are highly expressed in organ systems involved in the control of blood pressure and cardiac function. However, it is not known how the functions of multiple RGS proteins are integrated or whether they work interdependently to control G protein signaling in the cardiovascular system to maintain homeostasis. To address these questions, we have generated mice lacking both RGS2 and 5 (Rgs2/5 dbKO) concurrently. Although these mice are viable, they develop severe hypertension, have unprovoked cardiac hypertrophy, and the male mice are extremely sensitive to surgery-induced stress, causing death. The overall goals of the proposal are to determine the mechanisms that mediate augmented pathological phenotypes and death in Rgs2/5 dbKO mice, and to determine whether regulation of G protein signaling by RGS2 and 5 are coordinated to maintain normal cardiovascular physiology. We are poised to address the specific aims in this project by assembling all the necessary tools and expertise in molecular and cellular biology, echocardiography, biochemistry, and integrative physiology. Findings from this work will greatly enhance our understanding of G protein signaling regulation by RGS proteins in the cardiovascular system and elsewhere, thereby making a broad impact in the field.

标题：通过RGS蛋白进行的整合G蛋白信号转导调节的体内机制项目摘要 G蛋白信号转导参与许多生物系统的功能，包括神经，体液，自分泌和旁分泌系统，维持生理稳态。缺陷导致增加的G蛋白信号传导与许多病理生理学病症有关，最显著的是高血压和心脏病。因此，努力增加对G蛋白的了解，调节是了解疾病病因和开发更有效治疗方法的主要途径治疗心血管疾病G蛋白信号传导调节因子（Regulators of G protein signaling，RGS）通过调节G蛋白信号传导，作为GTP酶激活蛋白（GAP），加速GTP水解以终止G蛋白活性。许多RGS蛋白，包括R4/B亚家族的所有成员，在器官系统中高度表达参与控制血压和心脏功能。然而，目前尚不清楚这些功能是如何发挥作用的。多个RGS蛋白的整合，或者它们是否相互依赖地控制G蛋白在心血管系统中传递信号以维持体内平衡。为了解决这些问题，我们有产生同时缺乏RGS 2和5（Rgs 2/5dbKO）的小鼠。虽然这些老鼠是可以存活的，它们会发展成严重的高血压，并出现无缘无故的心脏肥大，对手术引起的压力极度敏感导致死亡该提案的总体目标是确定介导Rgs 2/5 dbKO中病理表型增强和死亡的机制小鼠，并确定RGS 2和5对G蛋白信号传导的调节是否协调，维持正常的心血管生理机能我们准备通过以下方式实现该项目的具体目标：集合所有必要的工具和专业知识，包括分子和细胞生物学，超声心动图，生物化学和综合生理学。这项工作的结果将大大提高我们的认识在心血管系统和其他地方通过RGS蛋白调节G蛋白信号传导，从而在该领域产生广泛影响。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons.

DOI：
10.1097/j.pain.0000000000002396
发表时间：
2022-04-01
期刊：
Pain
影响因子：
7.4
作者：
Xia J;Dou Y;Mei Y;Munoz FM;Gao R;Gao X;Li D;Osei-Owusu P;Schiffenhaus J;Bekker A;Tao YX;Hu H
通讯作者：
Hu H

Mitochondrial fission inhibition protects against hypertension induced by angiotensin II.

DOI：
10.1038/s41440-024-01610-0
发表时间：
2024-02
期刊：
Hypertension research : official journal of the Japanese Society of Hypertension
影响因子：
0
作者：
Kyle J. Preston;Tatsuo Kawai;Keiichi Torimoto;R. Kuroda;Yuki Nakayama;Tomoko Akiyama;Y. Kimura;Rosario Scalia;Michael V Autieri;Victor Rizzo;Tomoki Hashimoto;Patrick Osei-Owusu;Satoru Eguchi
通讯作者：
Kyle J. Preston;Tatsuo Kawai;Keiichi Torimoto;R. Kuroda;Yuki Nakayama;Tomoko Akiyama;Y. Kimura;Rosario Scalia;Michael V Autieri;Victor Rizzo;Tomoki Hashimoto;Patrick Osei-Owusu;Satoru Eguchi

Elastin haploinsufficiency accelerates age-related structural and functional changes in the renal microvasculature and impairment of renal hemodynamics in female mice.