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：
8189736
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/8189736
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. PUBLIC HEALTH RELEVANCE: The overarching goal of this proposal is to better understand how the kidney responds to a loss of blood supply, and how to prevent the subsequent damage that occurs. This is an important topic of study because acute kidney damage affects 15% of all people admitted to hospitals in the United States. This grant proposal coincides with the mandate of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K08 Mentored Clinical Scientist Development Award to encourage the development of promising young physician-scientists in an environment that promotes research excellence in kidney disease.

描述（由申请人提供）：这项修订的赠款提案概述了一个为期五年的肾脏学研究生涯的计划。首席研究员（PI）具有实验室调查的经验，并完成了肾脏学研究金培训。他目前正在发展急性肾脏损伤的调查和缺血和再灌注的部分。他将获得基思·赫鲁斯卡（Keith Hruska）博士的主要指导，他是血管疾病和肾脏损伤领域的国际认可的专家，并在培训医师科学家方面具有丰富的经验。 Hruska博士的专业知识将由一个科学咨询委员会提高，该委员会由个人组成，该委员会将在调查中为确定的领域提供帮助。 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，并得到了许多核心研究中心的补充。该提案的研究组成部分将集中在RGS4蛋白上，并在脉管系统和炎症细胞中具有已知功能。 G蛋白信号4（RGS4）调节剂的肾脏特异性活性将被研究，因为它适用于缺血和随后的再灌注损伤。缺血/再灌注肾脏损伤是急性肾脏疾病的最常见形式，但几乎没有治疗选择。 RGS蛋白有可能影响急性肾脏损伤的疾病过程，但是该研究领域在很大程度上没有探索。我们假设RGS4在肾脏缺血期间调节血管收缩，并减轻早期肾脏再灌注损伤的炎症反应。 RGS4已经在血管系统中识别活动。我们的发现表明，RGS4耗竭可降低急性缺血损伤后的肾血流，并因早期巨噬细胞的早期流入而复杂。研究工具将包括过表达RGS4的转基因小鼠模型，仅在血管平滑肌细胞中不表达RGS4，或者在全球范围内不表达RGS4。公共卫生相关性：该提案的总体目标是更好地了解肾脏如何应对失血的损失，以及如何防止随后造成的损害。这是一个重要的研究主题，因为急性肾脏损害影响了美国接受医院的所有人中有15％。这项赠款提案与国家糖尿病与消化研究所和肾脏疾病（NIDDK）K08的指导临床科学家发展奖的任务相吻合，以鼓励在促进肾脏疾病研究卓越研究的环境中发展有前途的年轻医师科学家。