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.
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.
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