Chagas disease, caused by Trypanosoma cruzi, the most common cause of congestive heart failure-related mortality and morbidity of humans, is endemic in Latin America. Continuous immigration from endemic areas of South and Central America has increased the risk of exposure of the U.S. population to chagas disease as well. The precise mechanisms leading to ventricular dilation and myocardial hypertrophy, observed in chagasic patients, are not well understood. The present studies are aimed at understanding the role of host gene regulation in the pathogenesis of chagasic cardiomyopathy. Our preliminary studies have suggested that the progression of chagasic myocarditis is associated with aberrations in the expression of cardiac contractile proteins and an imbalance in the mitochondrial energy metabolism proteins. In this project, we propose to investigate the molecular events that might affect the host mitochondrial function and initiate the imbalance of cytoskeletal proteins during the progression of chagas disease. Our hypothesis is that the inflammatory mechanisms elicited to control the pathogen might adversely affect the host mitochondria at the DNA, RNA or protein levels, resulting in a feedback cycle of progressively greater levels of reactive oxidant production and mitochondrial dysfunction. It is possible that reactive oxygen provides a stimuli for initiation of cardiac hypertrophy, and might be the critical determinant in reformatting of myocytes and loss of contractile function observed in chagasic patients. The proposed studies will determine the pathophysiological contribution of host mitochondrial abnormalities in the progression of chagas disease.
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