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Protein aggregation cardiomyopathy (PAC) (also termed desmin-related myopathy--DRM) is a life-threatening presentation of a multisystem disease caused by the exchange mutation in the gene encoding the human small HSP aB-crystallin (hR120GCryAB). Our major goal is to understand the pathogenic mechanisms by which hR120GCryAB expression causes cardiotoxicity and heart failure. Recent genetic studies in mice have shown that selective hR120GCryAB expression in the heart induces a novel toxic gain-of-function mechanism linked to increased activity of glucose 6-phosphate dehydrogenase (G6PD) mimicking reductive stress. Reductive stress refers to an abnormal increase of reducing equivalents (e.g., glutathione, NADPH), which has been demonstrated in lower eukaryotes but uncommonly in mammals and/or disease states. [Rajasekaran et. al, 2007, PDF]
Genetic evidence, that dysregulation of G6PD activity is a causal mechanism for R120GCryAB cardiomyopathy, raises several important questions and provides the thematic platform for programmatic support and research collaborations. What novel interactions between mutant CryAB and G6PD contribute to the pathogenesis of cardiomyocyte toxicity in R120GCryAB cardiomyopathy? Are other interacting factors necessary and sufficient for toxic gain-of-function mechanism in R120G cardiac disease? What are the molecular mechanisms and signaling pathways that contribute to increased G6PD activity? Does reductive stress exert direct or indirect consequences on mitochondrial (dys)function? What changes in gene expression occur before the onset of detectable myopathic or pathologic alterations, and how does redox imbalance regulate gene expression?
New NIH Grant:
Cardiologist Ivor J. Benjamin, MD, receives the prestigious NIH 2009 Pioneer Award. This $2.5 million award will allow Dr. Benjamin and his laboratory team and colleagues to research how "reductive stress" may damage the heart and other organs. Read the September 24, 2009 News Article
