Mechanisms of HSPB2 in Cardiac Metabolism and Ischemic Cardioprotection

描述（由申请人提供）：热休克蛋白（HSP）在蛋白质折叠、质量控制途径中发挥关键作用，是抗缺血/再灌注损伤的有效心脏保护剂。然而，该领域的一个基本但尚未解决的问题是，HSP家族的选择性成员是否在哺乳动物中以组织特异性的方式（如心脏）进化出了专门的角色。我们假设HSPB2是小MW HSP超家族的成员，包括CRYAB和HSP25，对心脏收缩性能、线粒体能量和防止细胞凋亡和坏死具有特殊的特性。然而，为了验证这一观点的有效性，有几个基本问题需要解决：细胞质中HSPB2表达的哪些功能和特性介导线粒体能量学？在DKO/mCryAB Tg小鼠中观察到的这种对心脏能量和功能的影响是否可以在一种新的组织特异性敲除hspb2中重现？hspb2缺乏的分子机制和信号通路有助于增加抵抗和矛盾的缺血性心脏保护？缺血损伤的持续时间和/或DKO缺乏的缺血环境是否模仿哺乳动物心脏中hspb2 KO小鼠的表型反应？HSPB2表达对线粒体功能有直接或间接影响吗？这些研究结果将有助于阐明HSPB2介导体内“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HSPB2在心肌细胞毒性和缺血性心脏保护的发病机制中的选择性表达。公共卫生相关性

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.