Oxidative Response Networks in Chagasic Cardiomyopathy

描述（由申请人提供）：慢性恰加斯型心肌病（CCM）是导致人类心力衰竭相关死亡率和发病率的主要原因。克氏锥虫是该病的病原，但临床疾病与寄生虫的存在无关，宿主因素可能参与了CCM发病机制的激活和/或维持。在最近的研究中，我们发现马达加斯加动物和患者存在呼吸链线粒体功能障碍。在功能水平上，线粒体损伤导致能量输出减少和氧化应激增加，这两者都在与CCM相关的心血管稳态中起关键作用。因此，在本提案中，我们计划研究线粒体功能障碍和氧化应激在人类恰加斯病严重程度中的关键重要性。我们的中心假设是，克氏锥虫感染引起心肌细胞的mt损伤，导致呼吸链效率低下和ROS形成的持续循环。这些ROS引起细胞氧化损伤，并导致人类chagasic患者心脏病理进展和左室功能受损。为了验证这一假设，我们将进行横断面研究，具体目的如下：1)确定mt的分子、生化和功能变化导致代谢活性受损，构成人类恰加斯病的危险因素；2)确定ros诱导的氧化细胞损伤如何增加患者出现恰加斯病临床症状的风险；3)确定mt和细胞氧化应激影响的分子途径，并参与进行性CCM过程中心肌结构和功能的改变。将分析其他病因的心肌病患者和健康受试者的样本进行比较。在完成拟议的研究后，我们期望证明氧化应激在CCM发展过程中煽动和/或维持病理过程（mt代谢改变，氧化过程，心脏重塑）中的重要性。与其他病因的心肌病患者的比较分析将提供对心肌病发展机制的深入了解，并确定抑制氧化反应是否有助于预防心脏损伤。我们期望找到新的靶点来开发组合疗法，以保护心肌细胞组成和心脏功能，这将有助于控制慢性心肌病的发病/进展。我们将与多个国家和国际合作者合作开展这些研究，因此，我们在阿根廷研究地点的合作者将获得尖端分子和生化方法的培训，从而提高他们在心血管传染病方面的研究能力。公共卫生相关性：拟议的研究将确定氧化应激反应途径和网络，增加恰加斯特（和其他）心肌病的易感性或进展。我们期望确定预防和治疗恰加斯病的新目标。

DESCRIPTION (provided by applicant): Chronic chagasic cardiomyopathy (CCM) is a major cause for heart failure related mortality and morbidity of humans. Trypanosoma cruzi is the etiological agent, however, clinical disease does not correlate with parasite presence, and host factors are likely involved in activation and/or sustenance of CCM pathogenesis. In recent studies, we have shown that chagasic animals and patients sustain mitochondrial dysfunction of respiratory chain. At functional level, mitochondrial damage resulted in a decrease in energy output and an increase in oxidative stress both of which can play a pivotal role in cardiovascular homeostasis associated with CCM. Thus, in this proposal, we plan to investigate the critical importance of mitochondrial dysfunction and oxidative stress in human Chagas disease severity. Our central hypothesis is that infection by T. cruzi elicits mt damage in cardiomyocytes that results in a continuing cycle of respiratory chain inefficiency and ROS formation. These ROS cause cellular oxidative damage, and lead to the development of progressive cardiac pathology and impaired LV function in human chagasic patients. To test this hypothesis, we will conduct a cross-sectional study with following specific aims: 1) Identify the molecular, biochemical, and functional changes in mt that cause impaired metabolic activity and constitute a risk factor in human Chagas disease, 2) Determine how ROS-induced oxidative cellular damage enhance the patients' risk to develop clinical symptoms of Chagas disease, and 3) Identify the molecular pathways that are affected by mt and cellular oxidative stress and contribute to myocardial structural and functional alterations during progressive CCM. Samples from cardiomyopathy patients of other etiologies and healthy subjects will be analyzed for comparison purposes. Upon completion of the proposed studies, we anticipate demonstrating the importance of oxidative stress in instigation and/or sustenance of pathological processes (mt metabolic alterations, oxidative processes, cardiac remodeling) during CCM development. The comparative analysis with cardiomyopathy patients of other etiologies would provide insight into the mechanisms of cardiomyopathy development, and identify whether inhibiting oxidative responses would be useful in preventing cardiac damage. We anticipate identifying novel targets for the development of combinatorial therapies for preserving the cardiomyocyte composition and heart function that will be useful in controlling the onset/progression of chronic cardiomyopathy. We will conduct these studies in collaboration with multiple national and international collaborators, and as a result, our collaborators at the Argentina study site will gain training in cutting edge molecular and biochemical approaches, thus, enhancing their research capabilities in cardiovascular infectious diseases. PUBLIC HEALTH RELEVANCE: The proposed studies will identify the oxidative stress response pathways and networks that enhance the susceptibility to or progression of chagasic (and other) cardiomyopathies. We anticipate identifying novel targets for prevention and treatment of Chagas disease.