Cytoprotective Role of HSP72 in Renal Cell Injury

描述（由申请方提供）：肾细胞死亡和缺血性急性肾损伤（阿基）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（阿基）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Hsp 70（Hsp 72 kDa）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阿基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。Hsp 70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）Hsp 70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Hsp 70预防线粒体断裂和Bax攻击的机制，并确定缺血性阿基的其他治疗靶点和（4）：在多大程度上可以预防缺血性阿基并加速肾脏恢复？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Hsp 70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。

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.