Trypanosoma cruzi-elicited cardiac hypertrophy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Cardiac hypertrophy is a critical step in the progression towards heart failure and a frequent consequence of chronic infections with the intracellular pathogen Trypanosoma cruzi, the causative agent of Chagas' disease in humans. The development of hypertrophy during Chagas' disease is likely to be complex, involving several cell types including cardiomyocytes, vascular smooth muscle and endothelial cells, and both parasite and host cell factors. Currently, little is known about the role of host cell or T. cruzi factors that may regulate chagasic cardiac hypertrophy. It was recently demonstrated that mediators of cardiac hypertrophy, including cardiotrophin-1 (CT-l), endothelin-1 (ET-l) and pro-inflammatory cytokines, are upregulated in the hearts of T. cruzi infected animals during acute experimental infection. To investigate whether T. cruzi infection of isolated cardiomyocytes is sufficient to activate hypertrophic response pathways in vitro, we examined the temporal expression of hypertrophic markers in cardiomyocytes following parasite infection. Our preliminary data indicate that infection of isolated cardiomyocytes with T. cruzi results in increased expression of a classical marker for cardiac hypertrophy, atrial natriuretic factor (ANF), and causes an increase in cell size. These novel results suggest that host cell responses induced early in infection by T. cruzi contribute directly to the pathogenic process, specifically cardiac hypertrophy. The goal of this proposal is to further characterize the hypertrophic response induced in cardiomyocytes by T. cruzi. We will determine the: relative contribution of parasite-activated signaling pathways and host cell factors produced during infection toward the T. cruzi induced hypertrophic response in cardiomyocytes. The specific aims of this study are to: (1) Characterize the T. cruzi stimulated hypertrophic response in isolated cardiomyocytes in vitro. (2) Determine the mechanism of T. cruzi-induced hypertrophy in vitro. (3) Characterize the hypertrophic response in hearts of T. cruzi infected mice and to correlate responses observed in vitro to those produced in the host during acute disease. Information generated from this research will immediately and significantly enhance the current understanding of the molecular basis for T. cruzi infection and pathogenesis. The long-term goal of this research is to understand how the complex interplay of signaling pathways in cardiomyocytes is altered during T. cruzi infection and how these events can influence the outcome of infection. With this knowledge, the potential exists to develop novel therapeutic strategies to reduce the risk of heart failure in Chagas' patients. Importantly, the training provided during this MCSDA will provide the necessary scientific and career development preparation to ensure the applicant a successful career as an independent investigator in the biomedical sciences.