Oxidative Response Networks in Chagasic Cardiomyopathy

慢性心肌病(CCM)是心力衰竭相关死亡和发病率的主要原因 人类的生命。克氏锥虫是克氏锥虫的病原体，但临床疾病与 寄生虫的存在和宿主因素可能参与了CCM发病的激活和/或维持。 在最近的研究中，我们已经证明查格症动物和患者存在线粒体功能障碍。 呼吸链。在功能水平上，线粒体损伤导致能量输出减少，并导致 氧化应激增加，这两者在心血管内稳态中都发挥着关键作用 CCM。因此，在这项提案中，我们计划调查线粒体功能障碍和 氧化应激在人类恰加斯病严重性中的作用。我们的中心假设是，感染克氏锥虫会引起mt. 心肌细胞的损伤，导致呼吸链无效和ROS的持续循环 队形。这些ROS导致细胞氧化损伤，并导致进行性心脏病的发生。 人类心脏失调症患者的病理和左心功能受损。为了验证这一假设，我们将进行一项 具有以下具体目标的横断面研究： 1)确定引起代谢活动受损的mt的分子、生化和功能变化 并构成人类恰加斯病的风险因素， 2)确定ROS诱导的氧化细胞损伤如何增加患者发展为临床的风险 恰加斯病的症状，以及 3)确定受线粒体和细胞氧化应激影响的分子途径 进展性CCM时心肌结构和功能的改变。 来自其他原因的心肌病患者和健康受试者的样本将被分析 比较的目的。在完成建议的研究后，我们预期会证明 氧化应激在病理过程中的煽动和/或维持(MT代谢改变， 氧化过程，心脏重构)在CCM发展过程中。与传统方法的比较分析 其他病因的心肌病患者将为心肌病的机制提供洞察力 发展，并确定抑制氧化反应是否有助于预防心脏病 损坏。我们期待着确定新的靶点，以开发组合疗法来保存 心肌细胞组成和心功能将有助于控制心肌梗死的发生和发展 慢性心肌病。 我们将与多个国家和国际合作者合作进行这些研究， 因此，我们在阿根廷研究地点的合作者将获得尖端分子和 生物化学方法，从而增强了他们在心血管传染病方面的研究能力。

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.