Trypanosoma cruzi-elicited cardiac hypertrophy

描述（由申请人提供）：心脏肥大是心力衰竭进展的关键步骤，也是慢性感染细胞内病原体克氏锥虫（恰加斯病在人类中的病原体）的常见后果。恰加斯病期间肥厚的发展可能是复杂的，涉及多种细胞类型，包括心肌细胞、血管平滑肌和内皮细胞，以及寄生虫和宿主细胞因素。目前，对宿主细胞或克氏t型细胞因子调控恰恰性心肌肥厚的作用知之甚少。最近的研究表明，心脏肥厚的介质，包括心营养因子-1 （ct -1）、内皮素-1 （et -1）和促炎细胞因子，在急性实验性感染克氏锥虫感染动物的心脏中上调。为了研究克氏锥虫感染分离心肌细胞是否足以激活体外肥厚反应通路，我们检测了寄生虫感染后心肌细胞中肥厚标志物的时间表达。我们的初步数据表明，感染克氏锥虫的分离心肌细胞会导致心脏肥厚的经典标志物心房钠尿因子（ANF）的表达增加，并导致细胞大小增加。这些新结果表明，克氏锥虫感染早期诱导的宿主细胞反应直接参与了致病过程，特别是心脏肥厚。

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.