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：
8210908
负责人：
Nisha Jain Garg
金额：
$ 35.82万
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 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8210908
关键词：
3-nitrotyrosine ATP2A2 Abbreviations Accounting Acute Affect Animals Antibodies Antioxidants Area Argentina Atrial Natriuretic Factor Biochemical Biochemistry Biogenesis Bioinformatics Biological Markers Biological Preservation Biology Biopsy Blood specimen Brain natriuretic peptide Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Cellular Morphology Cellular biology Cessation of life Chagas Disease Characteristics Chronic Chronic Disease Classification Clinical Collaborations Combined Modality Therapy Communicable Diseases Complex Creatine Kinase Creatinine Cross-Sectional Studies Custom Data Databases Defect Development Disease Disease susceptibility Echocardiography Electrocardiogram Engineering Enrollment Ensure Environment Enzymes Equilibrium Etiology Evolution Exhibits Experimental Models Extracellular Matrix Fibrosis Fluorescence Functional disorder Gene Expression Gene Proteins Genes Glutamates Glutathione Glutathione Disulfide Goals Health Heart Heart failure Homeostasis Hospitals Human Individual Infection Injury Institutes Integration Host Factors International Joints Laboratories Lead Left Ventricular Function Left ventricular structure Liquid Chromatography Liquid substance Luxon Malondialdehyde Manganese Superoxide Dismutase Metabolic Metabolism Mexico Mitochondria Mitochondrial Proteins Molecular Mus Myocardial Myosin Heavy Chains NADH dehydrogenase (ubiquinone)Organ Output Oxaloacetates Oxidants Oxidative Stress Oxidoreductase Parasite Control Parasites Pathogenesis Pathologic Pathologic Processes Pathologist Pathology Pathway interactions Patients Pattern Performance Peripheral Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phosphotransferases Plasma Plasma Proteins Play Positioning Attribute Predisposition Prevention Process Production Proteins Proteome Protocols documentation Pyruvate Reactive Oxygen Species Reagent Reduced Glutathione Research Respiratory Chain Reticulum Risk Risk Factors Role Sampling Scientist Serologic tests Severity of illness Signal Transduction Site Staging Structure Symptoms System Testing Tissues Training Transaminases Troponin Trypanosoma Trypanosoma cruzi Ventricular Remodeling Western Blotting base biological adaptation to stress cell injury combinatorial comparative design disability-adjusted life years experience gel electrophoresis glutathione peroxidase heart function heart rhythm human morbidity human subject innovation inorganic phosphate insight mitochondrial dysfunction mortality nitrone novel oxidation oxidative damage peripheral blood phenyl-N-tert-butylnitrone prevent respiratory response screening two-dimensional ubiquinol

项目摘要

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.

描述（由申请人提供）：慢性chagasic心肌病（CCM）是人类与心力衰竭相关的死亡率和发病率的主要原因。克鲁齐锥虫是病因，但是，临床疾病与寄生虫的存在无关，宿主因子可能参与CCM发病机理的激活和/或维持。在最近的研究中，我们表明chagasic动物和患者维持呼吸链的线粒体功能障碍。在功能水平上，线粒体损伤导致能量输出降低和氧化应激的增加，这两者都可以在与CCM相关的心血管稳态中起关键作用。因此，在该提案中，我们计划研究人类chagas疾病严重程度中线粒体功能障碍和氧化应激的关键重要性。我们的中心假设是，克鲁齐（T. cruzi）的感染引起了心肌细胞中MT损伤，从而导致呼吸链效率低下和ROS形成的持续循环。这些ROS会导致细胞氧化损伤，并导致人类chagasic患者的进行性心脏病理的发展和LV功能受损。为了检验这一假设，我们将进行以下特定目的进行横截面研究：1）确定MT中的分子，生化和功能变化，导致造成代谢障碍的危险因素，并构成人类Chagas疾病的危险因素，2）确定ROS诱导的氧化细胞损害如何增强患者的临床症状，并确定chagas病的风险，并确定chagas病的临床症状，并确定chagas症状的临床症状，并确定3）分子的临床症状，并确定3）。氧化应激并有助于进行性CCM期间的心肌结构和功能改变。将分析来自其他病因和健康受试者的心肌病患者的样本，以进行比较。拟议的研究完成后，我们预计将证明氧化应激在CCM发育过程中氧化应激在煽动和/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育机制的见解，并确定抑制氧化反应是否对预防心脏损伤有用。我们预计，可以识别出用于保留心肌细胞组成和心脏功能的组合疗法的新靶标，这将有助于控制慢性心肌病的发作/进展。我们将与多个国家和国际合作者合作进行这些研究，结果，我们在阿根廷研究站点的合作者将获得有关尖端分子和生化方法的培训，从而增强了他们在心血管传染病中的研究能力。