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Cytoprotective Role of HSP72 in Renal Cell Injury

HSP72 在肾细胞损伤中的细胞保护作用

基本信息

批准号：
8849429
负责人：
STEVEN C. BORKAN
金额：
$ 37.85万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8849429
关键词：
Acute Renal Failure with Renal Papillary Necrosis Apoptosis BCL-2 Protein BCL2 gene Bilateral Blood flow Cell Death Cell Nucleus Cell Survival Cessation of life Chemicals Chimeric Proteins Complex Cytosol Data Defect Disease Dominant-Negative Mutation Dynamin Epithelial Cells Epitopes Equilibrium Family Genetic Harvest Health Histologic Human Injury Intervention Ischemia Kidney Kidney Diseases Knockout Mice Life Measurement Measures Mediating Mitochondria Molecular Chaperones Morbidity - disease rate Morphology Mus Necrosis Nuclear Export Nuclear Import Organ Organ failure Outer Mitochondrial Membrane Pathway interactions Peptides Phosphorylation Phosphotransferases Point Mutation Predisposition Prevention Proteins Public Health Recovery Renal function Resistance Role Serine Serine Phosphorylation Site Signal Transduction Site Small Interfering RNA Stress Structure Testing Therapeutic Time Toxic effect caspase-3 cell injury in vivo kidney cell mitochondrial membrane mortality mutant novel novel strategies novel therapeutics nucleophosmin prevent protective effect renal ischemia therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Renal cell death and ischemic acute kidney injury (AKI) result from BCL2 protein-mediated mitochondrial membrane injury. How Bax, the quintessential "bad actor" of the BCL2 family causes outer mitochondrial membrane injury and renal cell death is uncertain. We hypothesize that interaction between conformationally active Bax and nucleophosmin (NPM), a recently described Bax chaperone, is required to form cytosolic complexes that translocate Bax to mitochondria, cause renal cell deat and impair kidney function. We propose that ischemic (AKI) can be inhibited at several steps by: reducing Bax activation, limiting NPM-Bax complex formation, or preventing mitochondrial fragmentation that increases mitochondrial susceptibility to "Bax Attack". Since Hsp70 (Hsp72kDa) likely interrupts the ischemic cell death pathway at each step, and a Bax blocking peptide prevents NPM-Bax complex formation, we anticipate that both maneuvers will be highly effective in preventing and accelerating recovery from ischemic AKI. In four AIMS, we will determine: (1) To what extent is conformational Bax activation during renal ischemia regulated by Akt or GSK3¿, stress kinases known to mediate renal cell survival. The protective role of Hsp70 on both Akt and GSK3¿ will be explored~ (2) To what extent is the nucleophosmin-Bax complex required for renal cell injury? We propose that renal ischemia causes regulated NPM translocation from the nucleus into the cytosol, where it complexes with active Bax, enhances mitochondrial Bax accumulation and cell death~ (3) How does Hsp70 decrease stress-induced mitochondrial fragmentation and increase resistance to Bax Attack? We will characterize the mechanism(s) by which Hsp70 prevents mitochondrial fragmentation and Bax Attack and identify additional therapeutic targets in ischemic AKI and (4): To what extent can ischemic AKI be prevented and renal recovery be accelerated? We propose that Hsp70 and a Bax blocking peptide, agents that limit NPM and Bax toxicity, will effectively prevent and treat renal ischemia in vivo. These studies identify new targets of renal ell death that are amenable to intervention and determine the efficacy of Hsp70 induction and disruption of NPM-Bax complex as therapeutic strategies for preventing or accelerating recovery from ischemic AKI, a major challenge to public health for which there is no current therapy.

描述（由申请方提供）：肾细胞死亡和缺血性急性肾损伤（AKI）由BCL 2蛋白介导的线粒体膜损伤引起。 Bax是BCL 2家族典型的"坏演员"，它如何导致线粒体外膜损伤和肾细胞死亡尚不确定。我们推测，构象活性Bax和核磷蛋白（NPM），最近描述的Bax分子伴侣之间的相互作用，需要形成胞质复合物的Bax易位到线粒体，导致肾细胞deat和损害肾功能。我们提出，缺血性（AKI）可以通过以下几个步骤抑制：减少Bax激活，限制NPM-Bax复合物的形成，或防止线粒体碎片，增加线粒体对“Bax攻击”的易感性。由于Hsp70（Hsp72kDa）可能在每个步骤中断缺血性细胞死亡途径， Bax阻断肽阻止NPM-Bax复合物的形成，我们预计这两种策略在预防缺血性AKI和加速其恢复方面都非常有效。在四个目标中，我们将确定：（1）Akt或GSK 3？（已知介导肾细胞存活的应激激酶）在肾缺血期间调节Bax构象激活的程度。Hsp70对Akt和GSK 3的保护作用有待进一步研究。（2）核磷蛋白-Bax复合物在肾细胞损伤中的作用程度如何？我们推测肾缺血可引起NPM从核转位到胞浆，在胞浆中与活性Bax复合，促进线粒体Bax的积累和细胞死亡。（3）Hsp70如何减少应激诱导的线粒体断裂，增强对Bax攻击的抵抗力？我们将描述Hsp70预防线粒体断裂和Bax攻击的机制，并确定缺血性AKI的其他治疗靶点和（4）：在多大程度上可以预防缺血性AKI并加速肾脏恢复？我们建议，热休克蛋白70和Bax阻断肽，代理限制NPM和Bax的毒性，将有效地预防和治疗肾缺血在体内。这些研究确定了适于干预的肾细胞死亡的新靶点，并确定了Hsp70诱导和NPM-Bax复合物破坏作为预防缺血性AKI或加速其恢复的治疗策略的功效，缺血性AKI是目前没有治疗方法的公共卫生的主要挑战。