Default Pathway of Apoptosis in Acute Renal Failure

描述（由申请人提供）： 这项研究职业奖申请的总体目标是了解细胞凋亡的默认途径在急性肾功能衰竭（ARF）发病机制中的作用。该申请的目的是提供啮齿动物急性肾衰竭模型和分子生物学技术方面的额外培训，以促进候选人过渡到与肾脏疾病相关的阿托提斯研究领域的独立科学家。以往关于凋亡在ARF中的作用的研究主要集中在细胞毒性刺激作为凋亡诱导剂。我们认为，肾小管细胞凋亡不仅是由于直接的细胞损伤，但也相对缺乏的生存因子。此外，我们认为生长因子在实验性ARF中的治疗效果部分是通过抑制细胞死亡和细胞凋亡的默认途径来介导的。我们的目标是通过两种方式来解决这些问题。体外方法将阐明信号通路和/或细胞内介质，通过这些信号通路和/或细胞内介质，在被剥夺所有可溶性存活因子的小鼠肾近端小管（MKPT）细胞中ERK 1/2的自发激活诱导Akt的下调并促进MKPT细胞凋亡。通过使用细胞信号传导和分子生物学工具，我们将剖析这种关系的机制，并使用基因阵列和转录因子分析，我们将映射在默认的凋亡途径过程中发生的下游事件。体内方法将使用分子方法检测ERK 1/2通路在实验性缺血性ARF阿金恢复中的作用。在ARF恢复期改善细胞凋亡的干预措施具有很大的治疗潜力，因为它们可以在ARF发作后施用，而无需预测ARF何时发生。候选人Vessel Patel是伊利诺伊大学芝加哥分校的讲师，Jerrold Levine、大卫Ucker、Jose Arruda、大卫Basile、Wil Leiberthal、Mike Abechtal和John Schwartz的培训团队由细胞凋亡和急性肾衰竭领域的知名专家组成。有机构承诺和涵盖广泛活动的综合职业发展计划。这些研究将提高我们对ARF默认途径的理解，并为Patel博士提供所需的严格培训，以促进他独立研究生涯的目标。此外，这些研究还有助于了解其他细胞和器官系统中细胞凋亡的默认途径。

DESCRIPTION (provided by applicant): The overall objective of this research career award application is to understand the role of the default pathway of apoptosis in the pathogenesis of acute renal failure (ARF). The goal of this application is to provide additional training in the rodent acute renal failure model and molecular biology technology to facilitate the candidates transition to an independent scientist in the field of apoptotis research relating to kidney disease. Previous studies on the role of apoptosis in ARF have focused on cytotoxic stimuli as inducers of apoptosis. We suggest that apoptosis of renal tubular cells is due not only to direct cellular injury but also to a relative deficiency of survival factors. Moreover, we suggest that the therapeutic efficacy of growth factors in experimental ARF is mediated, in part, through suppression of cell death and the default pathway of apoptosis. We aim to approach these questions in two ways. An in vitro approach will elucidate the signaling pathways and/or intracellular mediators by which spontaneous activation of ERK1/2 in Mouse Kidney Proximal Tubule (MKPT) cells deprived of all soluble survival factors induces down-regulation of Akt and promotes MKPT cell apoptosis. Through the use of cell signaling and molcular biology tools, we will dissect the mechanism of this relationship and with the use of gene array and transcription factor analysis we will map the downstream events occurring during the default pathway of apoptosis. The in vivo approach will examine the role of the ERK1/2 pathway in recovery from experimental ischemic ARF agin using molcular approaches. Interventions that ameliorate apoptosis during the recovery phase of ARF have great therapeutic potential, since they can be administered after the onset of ARF without the need to anticipate when ARF will occur. The candidate, Vimal Patel, is an Instructor at the University of Illinois, Chicago and the training team of Jerrold Levine, David Ucker, Jose Arruda, David Basile, Wil Leiberthal, Mike Abecassis and John Schwartz consists of established experts in the apoptosis and acute renal failure fields. There is institutional commitment and a integrated career development plan encompasing a broad range of activities. Taken together these studies will improve our understanding of the default pathway in ARF and provide Dr. Patel the rigorous training needed to facilitate his goal of an independent research career. Moreover, these studies should also help in understanding the default pathway of apoptosis in other cell and organ systems.