Apoptotic Gene Regulation in Renal Pathology

肾脏病理学中的凋亡基因调控

• 批准号: 7657264
• 负责人: Zheng Dong
• 金额: $ 26.58万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657264
• 关键词: Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Apoptosis; Apoptotic; Area; Bax protein; Binding; Caspase; Cell Death; Cell Nucleus; Cells; Chimeric Proteins; Cisplatin; Cytosol; Data; Development; Employee Strikes; Foundations; Gene Expression Regulation; Goals; Grant; Hand; In Vitro; Induction of Apoptosis; Injury; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Knockout Mice; Mediating; Membrane; Mitochondria; Modeling; Nephrotoxic; Oligonucleotides; Pathology; Phase; Physiological; Process; Protein Family; Proteins; Publishing; Recruitment Activity; Regulation; Research; Research Personnel; Role; Signal Transduction; Small Interfering RNA; Testing; Tubular formation; Work; apoptosis inducing factor; apoptotic protease-activating factor 1; base; cell injury; cytochrome c; experience; in vivo; kidney cell; knockout gene; mitochondrial dysfunction; mitochondrial membrane; nephrotoxicity; novel therapeutics; prevent; programs; reconstitution

DESCRIPTION (provided by applicant): The goal of this renewal project is to elucidate the apoptotic mechanism of tubular cell injury, a major cause of acute renal failure. During the last grant period, we and others have demonstrated the involvement of tubular cell apoptosis in ischemic and nephrotoxic renal injury. Importantly, these studies have suggested a pivotal role for mitochondrial damage and signaling. Under the pathological condition, the outer membrane of mitochondria is permeabilized, resulting in the release of apoptogenic factors such as cytochrome c. Mitochondrial membrane permeabilization involves the pro-apoptotic Bcl-2 family proteins, Bax and Bak; however, the underlying mechanism is unclear. Our preliminary studies have now revealed a striking morphological change of mitochondria during tubular cell apoptosis. Importantly, the morphological change appears to be a determinant of mitochondrial permeabilization. We found: 1) upon apoptosis induction, filamentous mitochondria become fragmented; 2) inhibition of mitochondrial fission or fragmentation prevents mitochondrial membrane permeabilization and apoptosis; 3) Drp-1, a fission protein, translocates to mitochondria during tubular cell apoptosis; 4) while both Bax and Bak contribute to mitochondrial permeabilization, Bak appears to have a unique role in mitochondrial fragmentation. We hypothesize that upon apoptosis induction, Drp-1 is recruited to mitochondria and collaborates with Bak to induce mitochondrial fission and fragmentation. Membrane changes during mitochondrial fragmentation facilitate the formation of apoptotic pores by Bax/Bak, leading to the release of apoptogenic factors. We will test this hypothesis by two specific aims. Aim 1 will demonstrate mitochondrial fragmentation in vivo and its role in acute kidney injury. Aim 2 will elucidate the regulation of mitochondrial morphological dynamics by Bak and Bax during apoptosis. The studies are expected to advance the fundamental understanding of mitochondrial injury during tubular cell apoptosis. Completion of the research may provide novel therapeutic strategies for ischemic and nephrotoxic renal failure.

描述（由申请人提供）：本更新项目的目的是阐明小管细胞损伤的凋亡机制，小管细胞损伤是急性肾功能衰竭的主要原因。在上一个资助期间，我们和其他人已经证明了小管细胞凋亡在缺血性和肾毒性肾损伤中的参与。重要的是，这些研究表明了线粒体损伤和信号传导的关键作用。病理状态下，线粒体外膜通透化，导致细胞色素c等凋亡因子释放。线粒体膜通透化涉及促凋亡的Bcl-2家族蛋白Bax和Bak；然而，潜在的机制尚不清楚。我们的初步研究现在已经揭示了线粒体在小管细胞凋亡过程中的显著形态变化。重要的是，形态变化似乎是线粒体通透性的决定因素。我们发现：1)细胞凋亡诱导后，丝状线粒体片段化；2)抑制线粒体分裂或断裂可阻止线粒体膜渗透和凋亡；3)小管细胞凋亡过程中裂变蛋白Drp-1易位至线粒体；4)虽然Bax和Bak都有助于线粒体通透性，但Bak似乎在线粒体断裂中起着独特的作用。我们假设在细胞凋亡诱导过程中，Drp-1被募集到线粒体，并与Bak协同诱导线粒体分裂和断裂。线粒体断裂过程中膜的改变促进Bax/Bak形成凋亡孔，导致凋亡因子的释放。我们将通过两个具体目标来检验这一假设。目的1将证明线粒体碎片在体内及其在急性肾损伤中的作用。目的2将阐明Bak和Bax在细胞凋亡过程中对线粒体形态动力学的调控。这些研究有望促进对小管细胞凋亡过程中线粒体损伤的基本认识。该研究的完成可能为缺血性和肾毒性肾功能衰竭提供新的治疗策略。