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

我们的长期目标是将SaMi-Trop建立为巴西被忽视的传染病研究的卓越中心。本申请的具体目标是通过关注T来开始该过程。cruzi感染，目的是找到一系列与寄生虫持续性和查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，以及用作新药治愈或疗效的替代标志物。我们将开展三项相互关联的研究：项目1将侧重于将基因表达工具应用于NHLBI REDS-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载量和抗体谱和滴度）和血浆蛋白质组学生物标志物（趋化因子、细胞因子和炎症、凝血和心脏参数），以生成与预定义的疾病阶段相关的复合生物标志物谱和评分。在项目2中，我们计划使用苯并咪唑（BZN）标准治疗治疗来自REDS-II队列的100例克氏锥虫PCR阳性患者，并在治疗后随访受试者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实用性，以评估治疗反应，包括寄生虫血症的清除或抑制或免疫扰动和心脏损伤标志物的正常化。在项目3中，我们计划利用米纳斯州的公共卫生系统，从2 000名南美锥虫病患者中登记和采集血样。这些患者将接受为期两年的随访，终点为死亡或因心脏病住院。主要目标是根据生物标志物水平和ECG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：行政核心和数据库及流行病学核心将支持三个项目的活动，并为巴西青年科学家建立和维持研究培训能力。

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.