Pathogenesis of Oxidative Stress in Chagas Disease

描述（由申请方提供）：查加斯病由原生动物克氏锥虫引起，是全球第三大热带疾病负担。查加斯病管理的年度总费用估计超过80亿美元。近年来，寄生虫的人畜共患存在和人口流动性增加，通过输血，先天性感染和器官移植传播，增加了美国的查加斯人类病例。然而，没有疫苗或安全的药物可用于治疗估计在美国> 300，000名患者和在流行国家> 1000万名患者。本项目的研究将确定治疗恰格曲病心肌病的治疗靶点。我们首先假设T. Cruzi通过三种不同的机制损害心脏组织：（1）伊卡+2应激是由入侵的寄生虫引起的，其导致线粒体膜电位的改变并引发活性氧（ROS）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，和（3）炎症诱导的免疫病理学的持续，特别是由于活性氧中间体。这些途径会聚，导致病理性肥大，导致心力衰竭。支持我们假设的主要初步观察结果包括：（1）T。抗氧化剂的cruzi表达增强了寄生虫的毒力，（2）宿主维持慢性氧化/炎性应激，这在查加斯病的进展期间有助于受损的LV功能，和（3）ROS诱导的DNA氧化加合物和聚（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性细胞因子应答的信号。我们将采用PI实验室建立的尖端分子，生物化学和免疫学工具，以实现以下三个目标-（1）测试Tc-抗氧化剂阻止受损细胞正常稳态清除的假设，并建立有利于纤维化的环境，（2）验证PARP-1/PAR下调Nrf 1/2通路并在慢性炎症/氧化状态中起关键作用的假设，和（3）检验抑制PARP-1将在预防脉络膜心肌病进展中提供治疗益处的假设。创新在于这样的想法，即寄生虫（抗氧化剂）和宿主（PARP-1/Nrf 1/2）分子通过心肌细胞中丰富的线粒体的相互作用是导致慢性炎症性心肌病演变的关键事件。这些研究意义重大，将证明抗寄生虫（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护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.