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：
9751200
负责人：
Nisha Jain Garg
金额：
$ 48.48万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751200
关键词：
Adult Affect Agonist Alternative Therapies American Binding Biogenesis Biological Assay Biopsy Cardiac Cardiac Myocytes Cardiomyopathies Cells Cessation of life Chagas Disease Chronic Chronic Phase of Disease Clinical Complex Congestive Heart Failure DNA Repair DNA Repair Gene DNA polymerase gamma DNA-Directed DNA Polymerase Defect Development Dilatation - action Dilated Cardiomyopathy Disease Equilibrium Etiology Experimental Models Failure Fibrosis Fluorescence Functional disorder Generations Genetic Glycolysis Guidelines Health Health Care Costs Heart Heart Diseases Heart failure Histones Homeostasis Human Immune Immunologic Receptors Impairment Individual Infection Inflammation Inflammatory Interferons International Latin American Link Longitudinal Studies Maintenance Measures Metabolic Mitochondria Mitochondrial DNA Molecular Mus Myocarditis Nuclear Oxidative Phosphorylation Oxides Parasites Pathology Patients Pentosephosphate Pathway Peripheral Blood Mononuclear Cell Phagocytosis Pharmaceutical Preparations Phenotype Pilot Projects Poly(ADP-ribose) Polymerases Polymerase Population Process Production Productivity Proteins Reactive Oxygen Species Receptor Signaling Respiratory Chain Risk Role SIRT1 gene Sampling Severities Signal Transduction Splenic Tissue Splenocyte Stress Testing Therapeutic Tissues Toxic effect Tropical Disease Trypanosoma cruzi Ventricular base burden of illness cell injury chagasic cardiomyopathy clinical risk cost cytokine design efficacy testing extracellular vesicles fatty acid oxidation human model inhibitor/antagonist innovation insight macrophage mouse model new therapeutic target novel novel therapeutics preservation prevent programs repaired respiratory response targeted delivery treatment strategy vesicular release

项目摘要

ABSTRACT Chagas disease, caused by Trypanosoma cruzi, represents the third greatest tropical disease burden. CD affects >7 million people, causes >17000 deaths, and costs ~$8.0 billion per year in health care costs and lost productivity. Infected individuals present oxidative and inflammatory stress, ventricular fibrosis and dilatation, and eventually develop congestive heart failure. In this project, we propose to examine a novel role of poly (ADP-ribose) polymerase 1 (PARP1) in chagasic pathology and offer an innovative potential therapy. Briefly, we believe that PARP1 cross-talk with mitochondrial DNA polymerase G (POLG) effects the mtDNA integrity, leading to a decline in respiratory chain efficiency and increase in mitochondrial reactive oxygen species (ROS) production in cardiomyocytes and chagasic heart. Moreover, phagocytosis of ROS-induced cell debris along with PARP1-dependent metabolic switch in macrophages signals activation and proliferation of proinflammatory macrophages. We will employ innovative, fluorescence-based, assays that measure multiple functional responses in the same sample to test our hypothesis in two specific aims. In aim 1, our objectives are to demonstrate that PARP1 activation increases the risk of clinical heart disease in infected patients, dissect how PARP1 interferes with mtDNA replisome with increasing severity of heart disease, and test that targeted delivery of PARP1 inhibitors to mitochondria preserves mitochondrial health and LV function in Chagas disease. In aim 2, our objectives are to test that extracellular vesicles (EV) produced due to ROS/PARP1-induced cellular injury carry the immune signature of chronic Chagas disease. We will demonstrate that EVs, in a disease stage-specific manner, engage intracellular innate immune receptors of macrophages, and macrophage expression of PARP1 provides metabolic signal for glycolytic switch and proinflammatory mφ activation. Importantly, we will test that controlling PARP1 activation is beneficial in silencing the tissue- destructive, inflammatory phenotype of chagasic patients’ macrophages. We believe the innovation lies in the idea of demonstrating how a DNA repair protein can disturb mitochondrial function and intensify inflammation. We will provide mechanistic insights into how these processes are linked and offer a novel therapy for preserving metabolic homeostasis and LV function in Chagas disease cases.

抽象的由克鲁兹锥虫引起的木马疾病代表了伯宁的第三大热带疾病。光盘影响> 700万人，导致> 17000人死亡，每年造成80亿美元的医疗保健费用，损失生产率。感染的个体表现出氧化和炎症应激，心室纤维化和扩张，并最终发展充血性心力衰竭。在这个项目中，我们建议研究聚（ADP-核糖）聚合酶1（PARP1）在 chagasic病理学并提供创新的潜在疗法。简而言之，我们相信PARP1与线粒体DNA聚合酶G（POLG）影响mtDNA完整性，导致呼吸链下降效率和线粒体活性氧（ROS）在心肌细胞和心脏。此外，ROS诱导的细胞碎片以及依赖PARP1代谢的吞噬作用巨噬细胞中的切换信号激活和促炎巨噬细胞的增殖。我们将雇用创新的，基于荧光的基于荧光的测定，测量同一样品中的多个功能响应以测试我们的假设在两个具体目标中。在AIM 1中，我们的目标是证明PARP1激活会增加临床心脏的风险感染患者的疾病，剖析PARP1如何干扰mtDNA复制体，严重程度增加心脏病和测试将PARP1抑制剂递送至线粒体可保留线粒体夏加斯病的健康和LV功能。在AIM 2中，我们的目标是测试由于ROS/PARP1引起的细胞外蔬菜（EV）细胞损伤带有慢性chagas病的免疫特征。我们将证明电动汽车在疾病阶段特异性的方式，参与巨噬细胞的细胞内先天免疫受体，并参与 PARP1的巨噬细胞表达为糖酵解开关和促炎Mφ提供了代谢信号激活。重要的是，我们将测试控制PARP1激活有益于使组织沉默破坏性的，chagasic患者巨噬细胞的炎症表型。我们认为，创新在于证明DNA修复蛋白如何干扰的想法线粒体功能并加剧炎症。我们将提供有关这些方式的机械见解过程是链接的，并提供了一种新的疗法，用于保存代谢稳态和LV功能查加斯病病例。