Trypanosoma cruzi-elicited cardiac hypertrophy

描述(申请人提供)：心肌肥厚是心力衰竭进展过程中的关键步骤，也是细胞内病原体克氏锥虫慢性感染的常见后果，克氏锥虫是人类查加斯病的病原体。Chagas病的肥大发展可能是复杂的，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，对宿主细胞或托克氏因子调节心肌肥厚的作用知之甚少。最近的研究表明，心脏肥大的介质，包括心肌营养素-1(CT-L)、内皮素-1(ET-L)和促炎性细胞因子，在急性实验性感染过程中，在动物心脏中上调。为了研究体外培养的心肌细胞感染克氏毛滴虫是否足以激活肥大反应通路，我们检测了寄生虫感染后心肌细胞肥大标志物的瞬时表达。我们的初步数据表明，克氏毛滴虫感染分离的心肌细胞会导致心肌肥大的经典标志物-心钠素(ANF)表达增加，并导致细胞大小增加。这些新的结果表明，克氏毛滴虫感染早期诱导的宿主细胞反应直接促进了致病过程，特别是心肌肥大。 这项建议的目的是进一步表征由克氏支原体诱导的心肌细胞肥大反应。我们将确定：寄生虫激活的信号通路和感染过程中产生的宿主细胞因子对克鲁兹毛滴虫诱导的心肌细胞肥大反应的相对贡献。本研究的具体目的是：(1)体外研究克氏毛滴虫刺激的心肌细胞肥大反应。(2)体外研究克氏毛滴虫诱导肥大的机制。(3)研究克氏毛滴虫感染小鼠心脏肥大反应的特征，并将体外观察到的反应与宿主在急性疾病期间所产生的反应相关联。 这项研究产生的信息将立即和显著地加强目前对克氏毛滴虫感染和发病机制的分子基础的了解。这项研究的长期目标是了解在克氏毛滴虫感染期间心肌细胞中复杂的信号通路的相互作用是如何改变的，以及这些事件如何影响感染的结果。有了这些知识，就有可能开发新的治疗策略来降低查加斯患者心力衰竭的风险。重要的是，在此次MCSDA期间提供的培训将提供必要的科学和职业发展准备，以确保申请者作为生物医学科学领域的独立研究人员取得成功。

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.