Sao Paulo- Minas Gerais Neglected Tropical Disease Research Center for Biomarker

我们的长期目标是将SaMi-Trop建立为巴西被忽视传染病研究卓越中心。当前申请的具体目标是通过关注克氏锥虫感染开始这一过程，目标是找到一系列与寄生虫持久性和恰加斯心脏病相关的生物标志物，这些生物标志物可用于推断疾病进展和死亡的风险，也可用作替代标志物治愈或新药的疗效。我们将开展三项相互关联的研究：项目1将专注于将基因表达工具应用于来自NHLBI red - ii队列的现有全血RNA样本，以发现和验证活动性感染和疾病进展的新生物标志物，这些生物标志物将与寄生虫特异性（PCR负载和抗体谱和滴度）和血浆蛋白质组学生物标志物（趋化因子、细胞因子、炎症、凝血和心脏参数）相结合，这些生物标志物正在通过已经资助的合作产生。生成与预先定义的疾病阶段相关的复合生物标志物概况和评分。在项目2中，我们计划使用苯并硝唑（BZN）的标准治疗治疗来自red - ii队列的100例T cruzi pcr阳性患者，并在治疗后随访2年。我们将使用这些样本来验证项目1中发现的生物标志物和复合生物标志物谱的效用，以评估治疗反应，包括清除或抑制寄生虫血症或免疫扰动的正常化和心脏损伤标志物。在项目3中，我们计划利用米纳斯州的公共卫生系统，招募并收集2000名南美锥虫病患者的血液样本。这些患者将被随访两年，以确定死亡或因心脏病入院的终点。主要目标是基于生物标志物水平和心电图结果获得一个简单的风险评分，可以识别高风险患者，以指导治疗方法并作为未来临床试验的基础。将建立两个核心：行政核心、数据库和流行病学核心，这两个核心将支持这三个项目的活动，并建立和维持巴西青年科学家的研究培训能力。

Our long term goal is to establish SaMi-Trop as a Center of Excellence for Neglected Infectious Disease Research in Brazil. The Specific Aims of the current application are to begin that process by focusing on T. cruzi infection with the goal of finding an array of biomarkers that correlate with parasite persistence and Chagas cardiac disease that can be used to infer risk of disease progression and death as well used as surrogate markers of cure or efficacy of novel drugs. We will develop three interrelated studies: Project 1 will focus on applying gene expression tools to existing whole blood RNA samples from the NHLBI REDS-II cohort to discover and validate new biomarkers of active infection and disease progression, these will be combined with parasite specific (PCR load and antibody profiling and titers) and plasma proteomic biomarkers (chemokines, cytokines, and inflamatory, coagulation and cardiac parameters) that are being generated through already funded collaborations, to generate composite biomarker profiles and scores that coorelate with pre-defined disease stages. In Project 2 we plan to treat a subgroup of 100 T cruzi PCR-positive patients from the REDS-II cohort using standard treatment with benznidazole (BZN) and follow subjects for 2 years after treatment. We will use these samples to validate the utility of biomarkers and composite biomarker profiles found in project 1 for assessment of therapeutic responses including clearance or suppression of parasitemia or normalization of immune perturbations and markers of cardiac damage. In Project 3 we plan to take advantage of the Public Health System in the State of Minas by enrolling and collecting blood samples from 2000 Chagas disease patients. These patients will be followed for two years for the endpoints of death or admission to a hospital for cardiac disease. The main goal is to obtain a simple risk score based on biomarker levels and ECG fndings that could identify high risk patients in order to guide therapeutic approaches and serve as a foundation for future clinical trials. Two cores will be established: the Administrative Core and Database and Epidemiology Core that will support activities of the 3 projects, as well as create and sustain research training capacity for young Brazilian scientists.