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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人类的。克氏锥虫是病原，但临床疾病与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。 In recent studies, we have shown that chagasic animals and patients sustain mitochondrial dysfunction of 呼吸链。 At functional level, mitochondrial damage resulted in a decrease in energy output and an 氧化应激的增加，这两者都可以在与心血管相关的稳态中发挥关键作用 CCM。 Thus, in this proposal, we plan to investigate the critical importance of mitochondrial dysfunction and 氧化应激影响人类恰加斯病的严重程度。 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 形成。这些 ROS 会引起细胞氧化损伤，并导致进行性心脏疾病的发生人类恰加斯病患者的病理学和左心室功能受损。为了检验这个假设，我们将进行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加患者发生临床症状的风险恰加斯病的症状，以及 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 比较目的。完成拟议的研究后，我们预计将证明其重要性 of oxidative stress in instigation and/or sustenance of pathological processes (mt metabolic alterations, CCM 发育过程中的氧化过程、心脏重塑）。与的对比分析 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 损害。 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 慢性心肌病。 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.