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、质量控制途径中起关键作用，是对抗缺血/再灌注损伤的有效心脏保护剂。然而，该领域一个基本但尚未解决的问题是，HSP家族的选择性成员是否以组织特异性方式（如心脏）在哺乳动物中进化出专门的作用。我们推测，HSPB 2，小分子量HSP超家族的成员，包括HSPAB和HSP 25，发挥专门的性质，心脏收缩性能，线粒体能量和保护细胞凋亡和坏死。然而，有几个基本问题需要解决，以测试这一想法的有效性：什么样的功能和性质的胞质HSPB 2表达介导线粒体能量？在DKO/mCryAB Tg小鼠中观察到的对心脏能量学和功能的这种影响是否会在新的组织特异性hspb 2敲除中重现？热休克蛋白b 2缺乏的分子机制和信号通路对增加抵抗力和矛盾的缺血性心脏保护作用有何贡献？DKO缺陷的缺血损伤和/或缺血环境的持续时间是否模拟哺乳动物心脏中hspb 2 KO小鼠的表型反应？HSPB 2的表达是否对线粒体功能产生直接或间接的影响？拟议的研究结果应有助于阐明的机制，HSPB 2介导的“经典”的应激反应在体内。利用组织特异性功能获得和功能丧失的小鼠突变体模型，我们的目的是了解选择性HSPB 2表达在心肌细胞毒性和缺血性心脏保护的发病机制。 公共卫生相关性 细胞蛋白质不断暴露于氧化和代谢应激，这改变了它们的基本结构并最终改变了功能。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，这些情况在缺血损伤后显著增加。这项研究计划将使用人类疾病的基因工程小鼠模型来研究HSPB 2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.