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

描述（由申请人提供）：这份修订后的资助提案概述了一个为期五年的肾脏学学术研究事业发展计划。首席研究员（PI）具有实验室调查经验，并完成了肾脏学奖学金培训。他目前正在研究急性肾损伤和缺血再灌注的组成部分。他将接受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，在医生-科学家培训方面拥有丰富的经验。一个由个人组成的科学咨询委员会将加强赫鲁斯卡博士的专业知识，他们将在与调查有关的特定领域提供协助。PI所在机构的学术环境为年轻科学家的职业发展提供了大量资源，并辅以许多核心研究中心。该提案的研究部分将集中在RGS4蛋白，已知在脉管系统和炎症细胞中具有功能。G蛋白信号传导调节因子4 （RGS4）的肾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/再灌注肾损伤是最常见的急性肾脏疾病，但治疗方法很少。RGS蛋白有可能影响急性肾损伤的疾病过程，但这一研究领域在很大程度上未被探索。我们假设RGS4调节肾缺血时的血管收缩，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，并与巨噬细胞的早期流入加剧。研究工具将包括转基因小鼠模型，这些小鼠模型过表达RGS4，不单独在血管平滑肌细胞中表达RGS4，或者不全局表达RGS4。

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.