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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063834-03
Application #
6527249
Study Section
Special Emphasis Panel (ZRG1-ECS (02))
Program Officer
Liang, Isabella Y
Project Start
2000-08-15
Project End
2003-06-30
Budget Start
2002-08-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$298,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Hussein, Rasha M; Benjamin, Ivor J; Kampinga, Harm H (2015) Rescue of ?B Crystallin (HSPB5) Mutants Associated Protein Aggregation by Co-Expression of HSPB5 Partners. PLoS One 10:e0126761
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Xie, Heng B; Cammarato, Anthony; Rajasekaran, Namakkal S et al. (2013) The NADPH metabolic network regulates human ?B-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster. PLoS Genet 9:e1003544
Brewer, Alison C; Mustafi, Soumyajit Banerjee; Murray, Thomas V A et al. (2013) Reductive stress linked to small HSPs, G6PD, and Nrf2 pathways in heart disease. Antioxid Redox Signal 18:1114-27
Limphong, Pattraranee; Zhang, Huali; Christians, Elisabeth et al. (2013) Modeling human protein aggregation cardiomyopathy using murine induced pluripotent stem cells. Stem Cells Transl Med 2:161-6
Benjamin, Ivor J (2012) Targeting endoglin, an auxiliary transforming growth factor ? coreceptor, to prevent fibrosis and heart failure. Circulation 125:2689-91
Christians, Elisabeth S; Benjamin, Ivor J (2012) Proteostasis and REDOX state in the heart. Am J Physiol Heart Circ Physiol 302:H24-37
Christians, Elisabeth S; Ishiwata, Takahiro; Benjamin, Ivor J (2012) Small heat shock proteins in redox metabolism: implications for cardiovascular diseases. Int J Biochem Cell Biol 44:1632-45

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