Cardiomyopathy is a consequence of infection with T.cruzi. Our lab has made progress in the elucidation of the biochemical and histopathological consequences of infection in a variety of in vitro and in vivo models. Our hypothesis is that infection with T.cruzi alters host cell function through changes in the receptor complexes notably the receptor units and coupling proteins. In the present proposal we shall examine the Beta adrenergic receptor with regard to quantification and characterization of density, affinity, and subtypes. In addition, we will characterize its interaction with the guanine nucleotide binding proteins, the coupling proteins, Gs and Gi. Similarly, guanine nucleotide proteins to which Beta receptors are linked will be characterized with regard to their identity, amount, activity and transcriptional regulation. These studies will focus on the characterization of their G proteins with regard to their ADP ribosylation by cholera and pertussis toxins. ADP-ribosylation, cyc-reconstitution assays, cDNA probes and antisera raised against sequence specific components of the G proteins will be employed. We have already demonstrated the ability of verapamil to ameliorate murine chagasic cardiomyopathy. This will be evaluated further by examining the Beta receptor complex in infected and uninfected mice treated with verapamil and other calcium channel blockers. In order to delineate those changes in the receptor complex that may be related to the clinical expression of the disease. Finally, we will determine the pharmacological and biochemical basis for the protection afforded by calcium channel blockers.
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