Default Pathway of Apoptosis in Acute Renal Failure

急性肾衰竭细胞凋亡的默认途径

• 批准号: 7260248
• 负责人: VIMAL PATEL
• 金额: $ 13.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7260248
• 关键词: Acute; Acute Kidney Failure; Apoptosis; Apoptosis Promoter; Award; Biology; Cell Death; Cells; Chicago; Development Plans; Down-Regulation; Event; Factor Analysis; Genes; Goals; Growth Factor; Illinois; In Vitro; Intervention; Kidney; Kidney Diseases; Kidney Failure; Maps; Mediating; Mediator of activation protein; Mentored Research Scientist Development Award; Molecular Biology; Molecular Models; Mus; Pathogenesis; Pathway interactions; Phase; Proximal Kidney Tubules; Range; Recovery; Relative (related person); Research; Rodent; Role; Scientist; Signal Pathway; Signal Transduction; Stimulus; Technology; Therapeutic; Training; Treatment Efficacy; Tubular formation; Universities; body system; career; cell injury; cytotoxic; improved; in vivo; instructor; tool; transcription factor

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.

描述（由申请人提供）： 该研究职业奖申请的总体目标是了解细胞凋亡默认途径在急性肾衰竭（ARF）发病机制中的作用。该申请的目标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细胞凋亡研究领域的独立科学家。先前关于细胞凋亡在 ARF 中的作用的研究主要集中在细胞毒性刺激物作为细胞凋亡的诱导剂。我们认为肾小管细胞的凋亡不仅是由于直接的细胞损伤，而且是由于生存因子的相对缺乏。此外，我们认为生长因子在实验性 ARF 中的治疗功效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解决这些问题。体外方法将阐明信号通路和/或细胞内介质，在缺乏所有可溶性生存因子的小鼠肾近端小管 (MKPT) 细胞中，ERK1/2 的自发激活可诱导 Akt 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，并通过使用基因阵列和转录因子分析，我们将绘制细胞凋亡默认途径期间发生的下游事件。体内方法将使用分子方法检查 ERK1/2 通路在实验性缺血性 ARF agin 恢复中的作用。在 ARF 恢复阶段改善细胞凋亡的干预措施具有巨大的治疗潜力，因为它们可以在 ARF 发作后进行，而无需预测 ARF 何时发生。候选人 Vimal Patel 是伊利诺伊大学芝加哥分校的讲师，Jerrold Levine、David Ucker、Jose Arruda、David Basile、Wil Leiberthal、Mike Abecassis 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。总而言之，这些研究将增进我们对 ARF 默认途径的理解，并为 Patel 博士提供所需的严格培训，以促进他实现独立研究生涯的目标。此外，这些研究还应有助于了解其他细胞和器官系统中细胞凋亡的默认途径。