Mechanisms of HSPB2 in Cardiac Metabolism and Ischemic Cardioprotection

描述(申请人提供)：热休克蛋白(HSP)在蛋白质折叠、质量控制途径中起关键作用，是有效的抗缺血/再灌注损伤的心脏保护剂。然而，该领域一个基本但尚未解决的问题是，热休克蛋白家族的选择性成员是否以组织特异性的方式(如心脏)在哺乳动物中进化出了特殊的角色。我们推测，HSPB2是包括CryAB和HSP25在内的小分子HSP超家族的成员，在心脏收缩功能、线粒体能量学以及对细胞凋亡和坏死的保护等方面发挥着特殊的作用。然而，为了测试这一观点的有效性，有几个基本问题需要解决：细胞质HSPB2表达的哪些功能和性质介导线粒体能量学？在DKO/mCryAB转基因小鼠中观察到的对心脏能量和功能的这种影响是否会在一种新的组织特异性hspb2基因敲除中重现？Hspb2缺乏导致抵抗力增加和反常的心肌缺血保护的分子机制和信号通路是什么？缺血损伤的持续时间和/或DKO缺乏症的缺血环境是否模拟哺乳动物心脏中hspb2KO小鼠的表型反应？HSPB2的表达对线粒体功能有直接或间接的影响吗？本研究的结果有助于阐明HSPB2在体内介导“经典”应激反应的机制。利用小鼠突变体的组织特异性功能获得和功能丧失模型，我们旨在了解选择性HSPB2表达在心肌细胞毒性和缺血心肌保护发病机制中的作用机制。公共卫生相关性 细胞蛋白质不断地暴露在氧化和代谢压力下，这改变了它们的基本结构和最终功能。热休克蛋白是进化上保守的蛋白质，其主要功能是作为分子伴侣防止蛋白质错误折叠和聚集，这种情况在缺血损伤后会显著增加。这项研究计划将利用人类疾病的基因工程小鼠模型来研究HSPB2对线粒体功能和心脏能量学的特定作用。

DESCRIPTION (provided by applicant): Heat shock proteins (HSP) play key roles in protein folding, quality control pathways and are potent cardioprotective agents against ischemia/reperfusion injury. Yet, a fundamental but unresolved question in the field is whether selective members of the HSP family have evolved specialized roles in a tissue-specific manner (such as the heart) in mammals. We hypothesize that HSPB2, a member of small MW HSP superfamily that includes CRYAB and HSP25, exerts specialized properties for cardiac systolic performance, mitochondrial energetics and protection against apoptosis and necrosis. There are, however, several fundamental issues that need to be resolved in order to test the validity of this idea: What functions and properties of cytosolic HSPB2 expression mediate mitochondrial energetics? Would such effects on cardiac energetics and function observed in DKO/mCryAB Tg mice be recapitulated in a novel tissue-specific knockout of hspb2? What molecular mechanisms and signaling pathways of hspb2 deficiency contribute to increased resistance and paradoxical ischemic cardioprotection? Do the duration of ischemic insult and/or the ischemic milieu of DKO deficiency mimic phenotypic responses of hspb2 KO mice in the mammalian heart? Does HSPB2 expression exert direct or indirect consequences on mitochondrial (dys)function? Results of the proposed studies should help elucidate the mechanism by which the HSPB2 mediates the `classical' stress response in vivo. Using tissue-specific gain-of-function and loss-of-function models of mouse mutants, we aim to understand the mechanisms of selective HSPB2 expression in the pathogenesis of cardiomyocyte toxicity and ischemic cardioprotection. PUBLIC HEALTH RELEVANCE Cellular proteins are constantly being exposed to oxidative and metabolic stresses, which alter their basic structure and ultimately function. Heat shock protein are evolutionarily conserved protein whose main functions as molecular chaperones prevent protein misfolding and aggregation, conditions that increase considerably following an ischemic insult. This research proposal will examine the specific roles of HSPB2 for mitochondrial function and cardiac energetics using genetically engineered mouse models of human diseases.