Biomarkers to Identify Individuals at RIsk for Progression of S. Japonicum Associated Hepatic Fibrosis with Point of Care Test Development

项目摘要 该热带医学研究中心（TMRC）的总体目标，为研究所的建议， 菲律宾热带医学中心（RITM）的主要任务是：a）执行本研究的关键科学目标，B）建立 RITM的研究能力，以及c）建立研究能力并支持初级研究人员的发展 与TMRC协调中心的“机会基金”和其他倡议合作，在所有TMRC 目前，吡喹酮（PZQ）预防性化疗策略是治疗 血吸虫病，每年或每两年提供“大规模药物管理”（MDA）。主要原因 肠型血吸虫病的严重发病率和死亡率的10%是肝内虫卵继发的门静脉纤维化 沉积，随后发生门静脉高压和食管静脉曲张，出血风险高。 重要的是，目前还没有建议来识别和更积极地治疗患有 在包括菲律宾在内的大多数地区，肝纤维化使个人很少接受治疗，如果有的话， 治疗目前，关于进展为更高级别门静脉纤维化的风险因素知之甚少， 包括生物标志物来识别风险。这是一个失去的机会，以减轻这一风险，通过更频繁的 治疗，这已被证明可以停止，甚至逆转纤维化，如果早期发现。我们的团队 开发了一种多路复用的“FibroPlex_v2”检测试剂盒，该试剂盒现在可以捕获38种与纤维增殖有关的关键分析物 或退化。我们将利用这一点来实现本研究的科学目标，即： 1)评估生物标志物，将确定个人与S。诊断为日本血吸虫相关性肝纤维化 通过基线时的超声（US）以及识别从轻度-中度进展至 美国每年评估的更高等级，为期三年 2)开发诊断测试，以帮助识别该领域的高风险个体，这些个体最终将 从更频繁的PZQ治疗或其他治疗方法中获益。我们预计许多分析物将 预测进展，这些将单独或组合开发为基于侧流的测定， 最终被开发为与MDA一起使用的POCT。 阻止进展的潜在治疗方法的可用性，缺乏逆转进展的方法， 一旦确定，门静脉周围纤维化分级，以及用于解决门静脉高压的次优干预措施 并且一旦确定其高死亡率，使其成为理想的筛选目标。生物标志物， 预测进展到不可逆等级的风险是至关重要的第一步。成功执行这些 aims还将建立RITM的研究能力，并通过以下方式为相关研究提供出色的机会： TMRC“机会基金”以及未来的赠款，以评估不同的治疗策略，为个人在 明确的随机对照试验显示，

PROJECT SUMMARY The overall goals of this Tropical Medicine Research Center (TMRC), proposed for the Research Institute of Tropical Medicine (RITM) in the Philippines, are to a) execute the key scientific aims of this study, b) build research capacity at RITM, and c) build research capacity and support the development of junior investigators at all TMRCs in partnership with the TMRC coordinating center’s “opportunity funds” and other initiatives Currently, preventative chemotherapy strategies with Praziquantel (PZQ) are the mainstay of treatment for schistosomiasis, with “mass drug administration” (MDA) delivered annually or bi-annually. The primary cause of severe morbidity and death due to intestinal schistosomiasis is portal fibrosis secondary to intra-hepatic egg deposition with consequent portal hypertension and esophageal varices with high risk of hemorrhage. Importantly, there are no current recommendations to identify and more aggressively treat individuals with hepatic fibrosis in most regions, including The Philippines, leaving individuals to receive infrequent, if any, treatment. Currently, little is known with respect to risk factors for progression to higher grade portal fibrosis, including biomarkers to identify risk. This is a lost opportunity to mitigate this risk through more frequent treatment, which has been shown to halt and even reverse fibrosis if identified early. Our groups have developed a multiplexed “FibroPlex_v2” assay that now captures 38 key analytes involved in fibro-proliferation or degradation. We will employ this to address the scientific goals of the study which are to: 1) Evaluate biomarkers that will identify individuals with S. japonicum associated hepatic fibrosis as diagnosed by ultrasound (US) at baseline as well as biomarkers that identify risk of progression from mild-moderate to higher grades as assessed by US annually for three years 2) To develop diagnostic tests to facilitate identification of high-risk individuals in the field who would ultimately benefit from more frequent treatment with PZQ or other treatment approaches. We expect many analytes will predict progression and these will be developed singly or in combination as lateral flow-based assays that can ultimately be developed as POCTs for use with MDA. The availability of potential treatment approaches to halt progression, the lack of approaches to reverse higher grade periportal fibrosis once established, and sub-optimal interventions for addressing portal hypertension and its high mortality rate once established, make this an ideal screening target. Biomarkers that longitudinally predict risk of progression to less reversible grades are a crucial first step. The successful execution of these aims will also build research capacity at RITM and provide outstanding opportunities for related studies through TMRC “opportunity funds” as well as future grants to evaluate different treatment strategies for individuals at risk for fibrosis progression with definitive randomized controlled trials.