Trypanosoma cruzi-elicited cardiac hypertrophy

克氏锥虫引起心脏肥大

• 批准号: 6735622
• 负责人: Christine A Petersen
• 金额: $ 1.75万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2004-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6735622
• 关键词: Trypanosoma cruzi; cardiac myocytes; host organism interaction; laboratory mouse; pathologic process; tissue /cell culture; trypanosomiasis; ventricular hypertrophy

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.

描述（由申请人提供）：心脏肥大是心力衰竭进展的关键步骤，也是细胞内病原体克氏锥虫（人类恰加斯病的病原体）慢性感染的常见后果。恰加斯病期间肥大的发展可能很复杂，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子。目前，人们对宿主细胞或克氏锥虫因子调节恰加斯心脏肥大的作用知之甚少。最近证明，在急性实验性感染期间，克氏锥虫感染的动物的心脏中心脏肥大的介质，包括心肌营养素-1(CT-1)、内皮素-1(ET-1)和促炎细胞因子，被上调。为了研究克氏锥虫感染分离的心肌细胞是否足以在体外激活肥大反应途径，我们检查了寄生虫感染后心肌细胞中肥大标记物的时间表达。我们的初步数据表明，用克氏锥虫感染分离的心肌细胞会导致心脏肥大的经典标记物心房钠尿因子（ANF）的表达增加，并导致细胞大小增加。这些新的结果表明，克氏锥虫感染早期诱导的宿主细胞反应直接导致致病过程，特别是心脏肥大。 该提案的目的是进一步表征克氏锥虫在心肌细胞中诱导的肥大反应。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氏锥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）表征体外分离心肌细胞中克氏锥虫刺激的肥大反应。 (2)确定克氏锥虫体外诱导肥大的机制。 (3) 表征克氏锥虫感染小鼠心脏肥大反应，并将体外观察到的反应与急性疾病期间宿主产生的反应相关联。 这项研究产生的信息将立即显着增强目前对克氏锥虫感染和发病机制的分子基础的理解。这项研究的长期目标是了解克氏锥虫感染期间心肌细胞信号通路的复杂相互作用如何改变，以及这些事件如何影响感染的结果。有了这些知识，就有可能开发出新的治疗策略来降低恰加斯患者心力衰竭的风险。重要的是，本次 MCSDA 期间提供的培训将提供必要的科学和职业发展准备，以确保申请人作为生物医学领域的独立研究者取得成功的职业生涯。