Apoptotic Gene Regulation in Renal Pathology

肾脏病理学中的凋亡基因调控

• 批准号: 7879034
• 负责人: Zheng Dong
• 金额: $ 2.47万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2012-07-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879034
• 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

The goal of this competitive renewal 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 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 and Endo-B1, two fission proteins, translocate to mitochondria during tubular cell apoptosis; 4) Endo-B1 specifically interacts with Bax; 5) 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, Endo-B1 interacts with Bax, leading to Bax translocation to mitochondria. Meanwhile, 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, leading to the release of apoptogenic factors. We will test this hypothesis by three specific aims. Aim 1 will demonstrate mitochondrial fragmentation in vivo and its role in acute kidney injury. Aim 2 will determine the involvement of Endo-B1 in Bax activation and mitochondrial fragmentation during tubular cell apoptosis. Aim 3 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.

这种竞争性更新的目标是阐明肾小管细胞损伤的凋亡机制，肾小管细胞损伤是一种主要的 急性肾功能衰竭的原因。在上一次赠款期间，我们和其他人已经证明了 肾小管细胞凋亡在缺血和肾毒性肾损伤中的作用。重要的是，这些研究表明 线粒体信号的关键作用。在病理条件下，血管外膜 线粒体被通透性，导致细胞色素c等促凋亡因子的释放。 线粒体膜通透性涉及促凋亡的Bcl2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揭示了一个惊人的 肾小管细胞凋亡过程中线粒体的形态变化。重要的是，形态的变化 似乎是线粒体通透性的决定因素。我们发现：1)在诱导细胞凋亡时， 丝状线粒体变得碎片化；2)抑制线粒体分裂或碎片化可防止 线粒体膜通透性与细胞凋亡；3)DRP-1和Endo-B1这两种分裂蛋白， 肾小管上皮细胞凋亡过程中移位到线粒体；4)Endo-B1与Bax特异性相互作用；5) Bax和Bak都有助于线粒体通透性，Bak似乎在线粒体通透性中具有独特的作用 线粒体碎裂。我们假设，在诱导细胞凋亡时，Endo-B1与Bax相互作用， 导致Bax易位到线粒体。同时，DRP-1被招募到线粒体并与之合作 用Bak诱导线粒体分裂和碎裂。线粒体过程中的膜变化 碎片化促进Bax形成凋亡孔，导致致凋亡素的释放 各种因素。我们将通过三个具体目标来检验这一假设。目标1将演示线粒体 体内碎裂及其在急性肾损伤中的作用。目标2将确定Endo-B1在 肾小管上皮细胞凋亡过程中Bax的激活和线粒体的碎裂。目标3将阐明 Bak和Bax对细胞凋亡过程中线粒体形态动力学的调节这些研究是 以期促进对肾小管上皮细胞凋亡过程中线粒体损伤的基础认识。 这项研究的完成可能会为肾缺血和肾毒性提供新的治疗策略 失败了。