THE ROLE OF REGULATOR OF G-PROTEIN SIGNALING 4 IN ACUTE KIDNEY INJURY

G 蛋白信号传导调节因子 4 在急性肾损伤中的作用

基本信息

批准号：
8661170
负责人：
Andrew Michael Siedlecki
金额：
$ 15.89万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8661170
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Advisory Committees Affect Angiotensin II Applications Grants Area Avidity Blood Vessels Bone Marrow Cell Culture Techniques Cells Complement Cyclosporine Development Diabetes Mellitus Digestive System Disorders Disease Endothelin A Receptor Endothelin-1 Environment Exhibits Fellowship G-Protein-Coupled Receptors GTP-Binding Protein Regulators GTP-Binding Proteins GTPase-Activating Proteins Goals Heterotrimeric GTP-Binding Proteins Hospitals Individual Inflammatory Inflammatory Response Injury Institutes Institution Investigation Ischemia Kidney Kidney Diseases Kidney Transplantation Knock-out Knockout Mice Laboratories Ligands Macrophage Activation Mediating Mentored Clinical Scientist Development Award (K08)Mentorship Mononuclear Mus Nephrology Phagocytes Phase Physicians Physiological Play Principal Investigator Process Program Development Proteins Publishing RGS Proteins Receptor Activation Renal Blood Flow Renal function Reperfusion Injury Reperfusion Therapy Reporting Research Research Project Grants Resources Role Scientist Signal Transduction Smooth Muscle Myocytes Therapeutic Time Training United States Vascular Diseases Vascular Endothelial Cell Vascular System Vascular blood supply Warm Ischemia Wild Type Mouse Work arteriole bosentan career career development density experience in vivo injured kidney vascular structure macrophage monocyte monocyte chemoattractant protein 1 receptor mouse model normotensive overexpression prevent protein activation renal ischemia research study response skills tool vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): This revised grant proposal outlines a five year program for the development of an academic research career in nephrology. The principal investigator (PI) has experience in laboratory investigation and completed nephrology fellowship training. He is currently developing his skills in the investigation of acute kidney injury and the component parts of ischemia and reperfusion . He will receive his primary mentorship from Dr. Keith Hruska, an internationally recognized expert in the field of vascular disease and kidney injury with extensive experience in the training of physician-scientists. Dr. Hruska's expertise will be augmented by a scientific advisory committee comprised of individuals who will provide assistance in defined areas germane to the investigation. The academic environment of the PI's institution has developed substantial resources for the career development of young scientists complemented by a host of core research centers. The research component of this proposal will focus on the RGS4 protein, with known function in the vasculature and inflammatory cells. The renal-specific activity of Regulator of G protein Signaling 4 (RGS4) will be investigated as it applies to ischemia and subsequent reperfusion injury. Ischemia/reperfusion kidney injury is the most common form of acute kidney disease and yet there are few therapeutic options. RGS proteins have the potential to influence the disease process of acute kidney injury, but this area of study is largely unexplored. We hypothesize that RGS4 regulates vasoconstriction during renal ischemia and mitigates the inflammatory response of early renal reperfusion injury. RGS4 has recognized activity in the vascular system. Our findings show RGS4 depletion decreases renal blood flow after acute ischemic injury and is compounded by an early influx of macrophages. Research tools will include genetically modified mouse models that, overexpress RGS4, do not express RGS4 in vascular smooth muscle cells alone, or do not express RGS4 globally.

描述（由申请人提供）：本修订后的拨款提案概述了肾病学学术研究职业发展的五年计划。主要研究者（PI）具有实验室调查经验并完成了肾脏病学进修培训。他目前正在研究急性肾损伤以及缺血和再灌注的组成部分方面的技能。他将得到 Keith Hruska 博士的主要指导，Keith Hruska 博士是血管疾病和肾损伤领域的国际公认专家，在培训医师科学家方面拥有丰富的经验。由个人组成的科学咨询委员会将增强赫鲁斯卡博士的专业知识，该委员会将在与调查密切相关的特定领域提供帮助。 PI 机构的学术环境为年轻科学家的职业发展开发了大量资源，并辅以众多核心研究中心。该提案的研究部分将重点关注 RGS4 蛋白，该蛋白在脉管系统和炎症细胞中具有已知的功能。将研究 G 蛋白信号传导调节器 4 (RGS4) 的肾脏特异性活性，因为它适用于缺血和随后的再灌注损伤。缺血/再灌注肾损伤是急性肾病最常见的形式，但治疗选择很少。 RGS 蛋白有可能影响急性肾损伤的疾病过程，但这一领域的研究很大程度上尚未被探索。我们假设 RGS4 在肾缺血期间调节血管收缩并减轻早期肾再灌注损伤的炎症反应。 RGS4 在血管系统中具有公认的活性。我们的研究结果表明，急性缺血性损伤后，RGS4 耗竭会减少肾血流量，并且巨噬细胞的早期流入会加剧这种情况。研究工具将包括过度表达 RGS4、仅在血管平滑肌细胞中不表达 RGS4 或全局不表达 RGS4 的转基因小鼠模型。