Chagas' disease is caused by Trypanosoma cruzi and is a major cause of morbidity and mortality in many areas of Latin American ranging from the Southern United States to Argentina. In up to 10-40% of those infected the heart will be compromised leading to death by heart failure in areas where the disease is endemic. Although not common the United States there are estimated to be more than 100,000 infected persons residing in this country where it has been suggested that cases will be encountered in increasing numbers. The pathogenesis of virtually all aspects of Chagas' disease continues to elude our knowledge. An understanding of the molecular mechanisms involved in parasite proliferation in the mammalian host could provide the basis for developing strategies to control T. cruzi infection. Recent studies from our laboratory have shown that epidermal growth factor (EGF), Transforming growth factor a (TGF-alpha) and Heparin Binding EGF (HB-EGF) bind specifically and selectively to the amastigote form of T. cruzi to induce growth within and outside host cells and that two monoclonal antibodies to the mammalian EGF receptor interact with a distinct surface protein of T. cruzi. The long term objective of this proposal is to understand the mechanisms by which these growth factors that bind to the EGF receptor modulate T. cruzi growth in mammalian host cells. The specific goal of this proposal is to begin to elucidate the signal transduction pathways induced by these growth factors on amastigotes. To this end we propose a) to study the induction of signal transduction events that occur after ligand binding to its receptor on the parasite surface; b) to study the internalization and down regulation of the EGF receptor in T. cruzi amastigotes following ligand binding to its receptor on the parasite surface; b) to study the internalization and down regulation of the EGF binding in T. cruzi amastigotes following ligand binding; c) to study the ability of other growth factors that bind to the EGF receptor to bind to the amastigote receptor and their biological relevance in experimental T. cruzi infections; d) to follow the internalization pathways of EGF receptor in a T. cruzi infected cell. These studies have the potential to elucidate novel mechanisms by which T. cruzi exploits pathways normally available to host cells to establish intracellularly. The fact that amastigotes have a growth factor receptor homologue provides a unique model to understand growth regulation of intracellular human pathogens. In the long run, identification of such novel mechanisms would lead to developing molecular means to control T. cruzi infection and other infectious diseases.
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