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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：
7567886
负责人：
Nisha Jain Garg
金额：
$ 37.95万
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 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7567886
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 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 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 Pyruvates Reactive Oxygen Species Reagent Reduced Glutathione Research Respiratory Chain Reticulum Risk Risk Factors Role Sampling Scientist Screening procedure Serologic tests Severities 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 public health relevance respiratory response 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. 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.

描述(申请人提供)：慢性心肌病(CCM)是导致人类心力衰竭相关死亡和发病率的主要原因。克氏锥虫是CCM的病原体，但临床疾病与寄生虫的存在无关，宿主因素可能参与了CCM发病的激活和/或维持。在最近的研究中，我们发现失弛缓症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CCM相关的心血管内稳态中发挥关键作用。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程度中的关键重要性。我们的中心假设是，克氏毛滴虫感染引起心肌细胞线粒体损伤，导致呼吸链无效和ROS形成的持续循环。这些ROS导致细胞氧化损伤，并导致人类心脏进行性病变和左心功能受损。为了验证这一假说，我们将进行一项横断面研究，目的如下：1)确定导致代谢活动受损并构成人类Chagas病风险因素的MT的分子、生化和功能变化，2)确定ROS诱导的氧化性细胞损伤如何增加患者出现Chagas病临床症状的风险，以及3)确定在进展性CCM过程中，MT和细胞氧化应激影响心肌结构和功能改变的分子途径。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以供比较。在拟议的研究完成后，我们预计将展示氧化应激在CCM发展过程中对病理过程(MT代谢改变、氧化过程、心脏重构)的激发和/或维持的重要性。与其他病因的心肌病患者的比较分析将有助于深入了解心肌病的发生机制，并确定抑制氧化反应是否有助于预防心脏损伤。我们期待为保护心肌细胞成分和心功能的组合疗法的发展找到新的靶点，这将有助于控制慢性心肌病的发生/进展。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化方法方面的培训，从而增强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，这些途径和网络增加了查格斯病(和其他)心肌病的易感性或进展。我们期待为恰加斯病的预防和治疗确定新的目标。