Pathogenesis of Oxidative Stress in Chagas Disease

描述（由申请人提供）：恰加斯病是由原生动物克氏锥虫引起的，是全球第三大热带疾病负担。南美锥虫病管理的年度总费用估计为80亿美元。近年来，寄生虫的人畜共患和人口流动的增加、通过输血传播、先天性感染和器官移植增加了美国的恰加斯病人间病例。然而，没有疫苗或安全药物可用于治疗美国约30万名患者和流行国家约1000万名患者。本项目的研究将确定恰加斯型心肌病的治疗靶点。我们提出了克氏绦虫通过三种不同的机制损害心脏组织的假设：(1)入侵寄生虫引起的iCa+2应激，导致mt膜电位的改变并启动活性氧（ROS）的释放；(2)寄生虫分子的直接作用促进受损宿主细胞的存活和细胞重塑；(3)炎症诱导的免疫病理的持续存在，特别是由于活性氧中间体。这些途径汇合，导致病理性肥厚导致心力衰竭。主要的初步观察结果支持了我们的假设，包括：(1)克氏T.表达抗氧化剂增强了寄生虫的毒力；(2)宿主维持慢性氧化/炎症应激，在恰加斯病的进展过程中导致左室功能受损；(3)ROS诱导的DNA氧化加合物和多（腺苷二磷酸核糖）聚合酶1 （PARP-1）激活在感染的心肌细胞中发出炎症细胞因子反应信号。我们将利用PI实验室建立的尖端分子，生化和免疫学工具，实现以下三个目标：(1)验证tc -抗氧化剂阻止受损细胞正常的稳态清除，并建立有利于纤维化的环境的假设；(2)验证PARP-1/PAR解除Nrf1/2通路并在慢性氧化/炎症状态中发挥关键作用的假设。(3)验证抑制PARP-1在预防恰加斯型心肌病进展中提供治疗益处的假设。创新之处在于，寄生虫（抗氧化剂）与宿主（PARP-1/Nrf1/2）分子通过心肌细胞内丰富的线粒体相互作用是导致恰加斯型心肌病慢性进化的关键事件。这些研究具有重要意义，并将证明针对寄生虫（抗氧化剂）和宿主（PARP-1/PAR）因子的治疗药物将在治疗急性感染和保存慢性感染患者的心脏功能方面提供最大的益处。

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.