The broad, long-term objective of this proposal is to elucidate the pathogenesis for the familial cardiomyopathy caused by the missense mutation in alphaB-crystallin (alphaBC) chaperone and to develop potential therapeutic strategies for similar cardiovascular disorders involving mutant proteins. Results of recent genetic analysis have established that a substitution of glycine for arginine at position 120 (Argl20Gly R120G) in the alphaB-crystallin protein causes an inheritable multisystem disorder leading to congestive heart failure and premature death. Presently, the nature of the unifying mechanism(s) and the pathogenesis of this cardiomyopathy is unknown. The hypothesis to be tested is that protein misfolding and aggregation of human alphaB-crystallin mutation (glycine yields arginine substitution at position 120, alphaBCR120G) are causal factors in the pathogenesis of the cardiomyopathy through effects that disorganize the cytoskeleton and impair contractile performance.
Specific aims i nclude: (1) Determine whether aggregate formation, a hallmark of the disease in the myocardium, is caused by protein misfolding and alphaB-crystallinR120G expression as a dominant defective allele; (2) Determine whether or not expression of human alphaB-crystallin gene alphaBC R120G impairs cardiac bioenergetics and increases ventricular dysfunction in the intact heart as assessed noninvasively using NMR spectroscopy, cardiac echocardiogram, and MRI imaging; (3) determine: (a) whether accumulation of the mutant alphaB-crystallinR120G protein evokes a bona fide 'unfolded protein response' and upregulation of the HSP family of stress 'heat shock' proteins, and (b) whether the posttranslational modifications affect mutant alphaB- crystallinR120G protein degradation. Our studies will employ transgenic and gene knock-out models of the alphaB-crystallin chaperone and the heat shock transcription factor. Results of this study should help elucidate the mechanisms by which the alphaB-crystallinR120G mutation causes cardiomyopathy. Evidence that endogenous protective mechanisms such as the HSP family of stress proteins can mitigate against or retard alphaB-crystallinR120G cardiomyopathy could have major implications for treatment of cardiovascular diseases involving either inherited or acquired genetic errors.
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