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

项目总结 热带医学研究中心(TMRC)的总体目标，为 菲律宾的热带医学(RITM)是a)执行这项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调查员的发展 在所有TMRC与TMRC协调中心的“机会基金”和其他倡议的合作下 目前，使用吡喹酮(PZQ)的预防性化疗策略是治疗肺癌的主要方法。 血吸虫病，每年或每两年提供一次“大规模药物管理”(MDA)。主要原因是 肠道血吸虫病的严重发病率和死亡率是肝内虫卵继发的门脉纤维化 伴随门脉高压和食道静脉曲张的沉积，出血的风险很高。 重要的是，目前还没有关于识别和更积极地治疗患者的建议 在包括菲律宾在内的大多数地区，肝纤维化使个人很少收到，如果有的话， 治疗。目前，关于进展为更高级别门脉纤维化的危险因素知之甚少。 包括识别风险的生物标记物。这是一个错失的机会，可以通过更频繁地 治疗，已被证明可以阻止甚至逆转纤维化，如果及早发现的话。我们的团队已经 开发了一种多路“FibroPlex_v2”分析方法，现在可以捕获38种与纤维增殖有关的关键分析物 或者退化。我们将利用这一点来解决这项研究的科学目标，即： 1)评估将日本血吸虫相关性肝纤维化诊断为个体的生物标记物 根据基线的超声(US)以及识别从轻-中度进展到 美国每年评估的较高等级，为期三年 2)开发诊断测试，以便于识别外地高危个人，这些人最终将 受益于更频繁地使用PZQ或其他治疗方法进行治疗。我们预计很多分析员会 预测进展，这些将单独或联合开发为基于横向流动的分析，可以 最终被开发为与MDA一起使用的POCT。 提供潜在的治疗方法来阻止进展，缺乏扭转病情升高的方法 门脉周围纤维化一旦建立，以及应对门脉高压的次优干预措施 一旦确定，它的高死亡率使其成为理想的筛查目标。纵向上的生物标志物 预测进展到较不可逆的等级的风险是关键的第一步。这些项目的成功执行 AIMS还将建设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”和未来的赠款，以评估不同的治疗策略的个人在 确定性随机对照试验的纤维化进展风险。

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.