Oxidative Response Networks in Chagasic Cardiomyopathy

摘要 由克氏锥虫引起的查加斯病是第三大热带疾病负担。CD 影响超过700万人，导致超过17000人死亡，每年花费约80亿美元的医疗保健费用和损失 生产力感染者表现为氧化和炎症应激，心室纤维化和扩张， 最终发展为充血性心力衰竭 在这个项目中，我们建议检查一个新的作用，聚（ADP-核糖）聚合酶1（PARP 1）， 改变病理学，并提供一种创新的潜在疗法。简而言之，我们认为PARP 1与 线粒体DNA聚合酶G（POLG）影响线粒体DNA的完整性，导致呼吸链功能下降 心肌细胞中线粒体活性氧（ROS）产生的效率和增加， 懊恼的心此外，ROS诱导的细胞碎片的吞噬沿着PARP 1依赖的代谢产物， 巨噬细胞中的转换发出促炎性巨噬细胞活化和增殖的信号。我们会委聘 创新的、基于荧光的检测方法，可测量同一样本中的多种功能反应， 我们的假设有两个具体目标。 在目标1中，我们的目标是证明PARP 1激活增加临床心脏病的风险。 疾病的感染患者，剖析如何PARP 1干扰线粒体DNA复制体与日益严重的 心脏病，并测试PARP 1抑制剂向线粒体的靶向递送保留了线粒体 健康和左心室功能。 在目的2中，我们的目标是测试由于ROS/PARP 1诱导的细胞外囊泡（EV）的产生， 细胞损伤带有慢性恰加斯病的免疫特征。我们将证明，电动汽车，在一个 疾病阶段特异性方式，参与巨噬细胞的细胞内先天免疫受体， 巨噬细胞表达PARP 1为糖酵解开关和促炎性Mφ提供代谢信号 activation.重要的是，我们将测试控制PARP 1激活有利于沉默组织- chagglutinase患者的巨噬细胞的破坏性，炎症表型。 我们相信创新在于展示DNA修复蛋白如何干扰 线粒体功能和加剧炎症。我们将提供机械的见解，如何这些 这些过程是相互联系的，并提供了一种新的治疗方法，用于保护代谢稳态和左室功能， 查加斯病病例。

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.