Oxidative Response Networks in Chagasic Cardiomyopathy

恰加斯心肌病的氧化反应网络

基本信息

批准号：
7994825
负责人：
Nisha Jain Garg
金额：
$ 36.68万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994825
关键词：
3-nitrotyrosine ATP2A2 Accounting Acute Affect Animals Antibodies Antioxidants Area Argentina Biochemical Biogenesis Bioinformatics Biological Markers Biological Preservation Biopsy Blood specimen Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Cellular Morphology Cessation of life Chagas Disease Characteristics Chronic Chronic Disease Clinical Collaborations Communicable Diseases Complex Cross-Sectional Studies Custom Data Defect Development Disease Disease susceptibility Echocardiography Electrocardiogram Enrollment Enzymes Equilibrium Etiology Evolution Exhibits Experimental Models Extracellular Matrix Fibrosis Fluorescence Functional disorder Gene Expression Gene Proteins Genes Glutathione Glutathione Disulfide Goals Heart Heart failure Homeostasis Human Individual Infection Injury Integration Host Factors International Lead Left Ventricular Function Left ventricular structure Liquid substance Malondialdehyde Manganese Superoxide Dismutase Metabolic Metabolism Mexico Mitochondria Mitochondrial Proteins Molecular Mus Myocardial Organ Output Oxidants Oxidative Stress Parasite Control Parasites Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Patients Performance Peripheral Pharmaceutical Preparations Phase Plasma Plasma Proteins Play Predisposition Prevention Process Production Proteins Proteome Reactive Oxygen Species Research Respiratory Chain Risk Risk Factors Role Sampling Serologic tests Severity of illness Signal Transduction Site Structure Symptoms System Testing Tissues Training Troponin Trypanosoma cruzi Ventricular Remodeling Western Blotting base biological adaptation to stress cell injury combinatorial comparative design disability-adjusted life years gel electrophoresis glutathione peroxidase heart function heart rhythm human morbidity insight mitochondrial dysfunction mortality nitrone novel oxidation oxidative damage peripheral blood prevent respiratory response two-dimensional

项目摘要

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.

慢性恰加斯心肌病（CCM）是心力衰竭相关死亡率和发病率的主要原因克氏锥虫是人类的病原体，但临床疾病与此无关。寄生虫的存在和宿主因素可能参与 CCM 发病机制的激活和/或维持。在最近的研究中，我们发现恰加斯病动物和患者维持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呼吸链下降。氧化应激增加，这两者都可以在与心血管相关的稳态中发挥关键作用因此，在本提案中，我们计划研究线粒体功能障碍和线粒体功能障碍的重要性。氧化应激对人类恰加斯病严重程度的影响我们的中心假设是克氏锥虫感染会引发 mt。在心肌细胞中，导致呼吸链效率低下和 ROS 持续循环这些活性氧的形成会导致细胞氧化损伤，并导致进行性心脏的发展。为了检验这一假设，我们将进行一项人类恰加斯病患者的病理学和左心室功能受损的研究。具有以下具体目标的横断面研究： 1) 识别导致代谢活动受损的 mt 的分子、生化和功能变化并构成人类恰加斯病的危险因素， 2) 确定 ROS 诱导的氧化细胞损伤如何增强患者的疗效？发展临床风险恰加斯病的症状，以及 3) 确定受 mt 和细胞氧化应激影响并有助于进行性 CCM 期间心肌结构和功能的改变。来自其他病因的心肌病患者和健康受试者的样本将被分析完成拟议的研究后，我们预计会证明其重要性。氧化应激在病理过程（mt代谢改变， CCM 发展过程中的氧化过程、心脏重塑）的比较分析。其他病因的心肌病患者将提供对心肌病机制的深入了解发展，并确定抑制氧化反应是否有助于预防心脏病我们预计会确定新的靶标来开发保护损伤的组合疗法。心肌细胞组成和心脏功能有助于控制疾病的发作/进展慢性心肌病。我们将与多个国家和国际合作者合作进行这些研究，并且因此，我们在阿根廷研究基地的合作者将获得尖端分子和生化方法，从而提高他们在心血管传染病方面的研究能力。