Pathogenesis of Oxidative Stress in Chagas Disease

恰加斯病氧化应激的发病机制

基本信息

批准号：
8825396
负责人：
Nisha Jain Garg
金额：
$ 34.43万
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：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8825396
关键词：
3-Dimensional 3-nitrotyrosine 4 hydroxynonenal 8-hydroxyguanosine Abbreviations Acute Adenosine Diphosphate Ribose Animals Antioxidants Apoptosis Apoptotic Biochemical Biogenesis Biological Assay Biological Preservation Blood Transfusion CREB-binding protein Cardiac Cardiac Myocytes Cardiomyopathies Cell Membrane Permeability Cells Cessation of life Chagas Disease Chronic Chronic Disease Clinical Congestive Heart Failure Country Cytokine Gene DNA Developed Countries Development Dilated Cardiomyopathy Disease Management Emerging Communicable Diseases Environment Evaluation Event Evolution Exhibits Fibrosis Flow Cytometry Fluorescein Fluorescence Microscopy Gap Junctions Gene Expression Generations Grant Healthcare Heart Heart failure Human Hypertrophy Immunochemistry Immunoprecipitation In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Pathway Invaded Iodides Laboratories Latin America Light Link Luciferases Malondialdehyde Manganese Superoxide Dismutase Membrane Potentials Metabolic Microscopy Mitochondria Modeling Molecular Molecular Analysis Morbidity - disease rate Mus Nuclear Organ Transplantation Outcome Oxidative Stress Parasites Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Play Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Polymerase Polymers Population RNA Interference Reactive Oxygen Species Recombinants Reporter Reverse Transcriptase Polymerase Chain Reaction Risk Factors Severities Signal Transduction Source Stress Testing Therapeutic Time Tissues Tropical Disease Trypanosoma cruzi Vaccines Ventricular Virulence Western Blotting adduct base burden of illness cell injury congenital infection cost cyanine dihydroethidium heart function hemodynamics human CREBBP protein human SOD2 protein immunopathology improved in vivo inhibitor/antagonist innovation migration multi-photon nitrone novel prevent reactive oxygen intermediate research study response second harmonic targeted treatment tetramethylrhodamine therapeutic target tool transmission process tryparedoxin peroxidase

项目摘要

DESCRIPTION (provided by applicant): Chagas disease is caused by the protozoan Trypanosoma cruzi, and represents the third greatest tropical disease burden globally. The total annual cost of Chagas disease management is estimated at >8 billion US dollars. The zoonotic presence of parasite and increased population mobility, transmission through blood transfusion, congenital infection and organ transplantation has, in recent years, increased the human cases of Chagas in the US. However, no vaccines or safe drugs are available for treatment of an estimated >300,000 patients in the US and >10 million patients in endemic countries. The studies in this project will identify therapeutic targets for the treatment of Chagasic cardiomyopathy. We pioneer the hypothesis that T. cruzi damages the heart tissue via three distinct mechanisms: (1) iCa+2 stress is caused by invading parasites, which results in alteration of mt membrane potential and initiates reactive oxygen species (ROS) release, (2) direct effects of parasite molecules promote survival of damaged host cells and cellular remodeling, and (3) persistence of inflammation-induced immunopathology, particularly due to reactive oxygen intermediates. These pathways converge, resulting in pathological hypertrophy leading to heart failure. The major preliminary observations that provide support to our hypothesis include (1) T. cruzi expression of antioxidants enhanced parasite virulence, (2) host sustains chronic oxidative/inflammatory stress that was contributory to impaired LV function during the progression of Chagas disease, and (3) ROS induced DNA oxidative adducts and poly(adenosine diphosphate ribose) polymerase 1 (PARP-1) activation signaled inflammatory cytokine response in infected cardiomyocytes. We will employ cutting-edge molecular, biochemical and immunological tools, established in the PI's laboratory, to achieve the following three aims - (1) Test the hypothesis that Tc-antioxidants prevent the normal homeostatic clearance of the damaged cells, and establish an environment conducive to fibrosis, (2) Test the hypothesis that PARP-1/PAR deregulates Nrf1/2 pathway and play a key role in chronic oxidative/inflammatory state of chagasic heart, and (3) Test the hypothesis that inhibition of PARP-1 will provide therapeutic benefits in preventing progression of chagasic cardiomyopathy. The innovation lies in the idea that the interaction of parasite (antioxidants) and host (PARP-1/Nrf1/2) molecules via abundant mitochondria in the cardiomyocytes is the key event resulting in chronic evolution of chagasic cardiomyopathy. These studies are significant and will demonstrate that therapeutic drugs against parasite (antioxidants) and host (PARP-1/PAR) factors will provide the most benefit in treatment of acute infection and preservation of heart function in chronically infected patients.

描述（由申请人提供）：Chagas病是由Cruzi原生动物锥虫引起的，代表了全球第三大热带疾病负担。夏加斯病管理的年总成本估计为80亿美元。近年来，寄生虫的人畜共患病的存在和增加的人口迁移，先天性感染和器官移植的传播增加了美国的人类chagas病例。但是，在美国估计估计> 300,000名患者，在流行国家中估计> 1000万患者，尚无疫苗或安全药物的治疗。该项目的研究将确定治疗chagasic心肌病的治疗靶标。我们先驱一个假说，即克鲁兹（T. cruzi）通过三种不同的机制损害心脏组织：（1）ICA+2压力是由入侵寄生虫引起的，这导致MT膜电位的改变，并引发活性氧（ROS）释放，（2）寄生虫分子的直接影响促进了寄生虫的宿主和细胞炎性宿主的生存，并促进了Rebiarm-Rebiant-Rebiand＆Replist and（3），并且（3）和3. 3（3）和3. 3）和3. 3（3），并促进了（3），并且（3）和3. 3（3），并促进了（3），并且（3）且（3）和寄生的宿主分子促进了宿主的生存，并促进了（3）和宿主的生存。免疫病理学，特别是由于活性氧中间体。这些途径融合，导致病理肥大导致心力衰竭。为我们的假设提供支持的主要初步观察包括（1）抗氧化剂的T. cruzi表达抗氧化剂增强的寄生虫毒力，（2）宿主持续持续的慢性氧化/炎症应激，这是降低了LV功能受损的lv功能，在摄氏降解和（3）ROS氧化剂添加剂（3）ROS氧化添加剂（3））（PARP-1）激活表明感染心肌细胞中的炎症细胞因子反应。 We will employ cutting-edge molecular, biochemical and immunological tools, established in the PI's laboratory, to achieve the following three aims - (1) Test the hypothesis that Tc-antioxidants prevent the normal homeostatic clearance of the damaged cells, and establish an environment conducive to fibrosis, (2) Test the hypothesis that PARP-1/PAR deregulates Nrf1/2 pathway and play a key role in chronic chagasic心脏的氧化/炎症状态，以及（3）检验抑制PARP-1的假设将在防止chagasic心肌病的进展方面提供治疗益处。创新在于寄生虫（抗氧化剂）和宿主（PARP-1/NRF1/2）通过大量心肌细胞中的线粒体的相互作用（PARP-1/NRF1/2）的相互作用是关键事件。这些研究很重要，将证明针对寄生虫（抗氧化剂）和宿主（PARP-1/PAR）的治疗药物将为慢性感染患者的急性感染和心脏功能保留提供最大的好处。