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

通过护理测试开发来识别有日本血吸虫相关肝纤维化进展风险的个体的生物标志物

• 批准号: 10434390
• 负责人: JENNIFER F FRIEDMAN
• 金额: $ 63.2万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434390
• 关键词: Address; Age; Animal Model; Antigens; Area; Area Under Curve; Biological Assay; Biological Markers; Blood specimen; Case Fatality Rates; Cessation of life; Cicatrix; Country; Deposition; Development; Diagnostic tests; Early treatment; Esophageal Varix; Evaluation; Fibrosis; Funding Opportunities; Future; Gastroenterology; Goals; Grant; Guidelines; Helminths; Hemorrhage; Human; Individual; Infection; Intervention; Intestines; Lateral; Liver; Liver Fibrosis; Metalloproteases; Morbidity - disease rate; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Philippines; Portal Hypertension; Praziquantel; Preventive treatment; Process; Production; Protocols documentation; Pulmonary Fibrosis; Randomized Controlled Trials; Recommendation; Research; Research Institute; Research Personnel; Risk; Risk Factors; Rupture; Schistosoma; Schistosoma japonicum; Schistosomiasis; Secondary to; Serum; Time; Tissues; Tropical Medicine; Ultrasonography; base; chemotherapy; egg; equipment acquisition; high risk; inhibitor; intrahepatic; low and middle-income countries; mortality; novel marker; point of care testing; predictive marker; recruit; research clinical testing; response; screening; specific biomarkers; surgical risk; synthetic polymer Bioplex; treatment strategy; ultrasound

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.

项目概要 该热带医学研究中心（TMRC）的总体目标是为热带医学研究所提出的 菲律宾热带医学 (RITM) 将 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) 建设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”和其他举措合作，在所有 TMRC 开展 目前，吡喹酮（PZQ）的预防性化疗策略是治疗的主要方法。 血吸虫病，每年或每两年进行一次“大规模药物管理”（MDA）。 肠血吸虫病导致严重发病和死亡的主要原因是肝内虫卵继发的门脉纤维化 沉积导致门静脉高压和食管静脉曲张，出血风险很高。 重要的是，目前没有建议来识别和更积极地治疗患有此病的个体 包括菲律宾在内的大多数地区都有肝纤维化，导致个人很少（如果有的话）接受肝纤维化治疗。 目前，对于进展为高级门静脉纤维化的危险因素知之甚少， 包括生物标志物来识别风险，这是一个通过更频繁地减轻这种风险的机会。 治疗已被证明，如果及早发现，可以阻止甚至逆转纤维化。 开发了一种多重“FibroPlex_v2”测定法，现在可捕获参与纤维增殖的 38 种关键分析物 我们将利用它来实现研究的科学目标，即： 1) 评估生物标志物，以识别诊断出的日本血吸虫相关肝纤维化患者 通过基线超声（US）以及识别从轻度到中度进展为风险的生物标志物 三年内每年由美国评估的更高成绩 2) 开发诊断测试，以促进现场识别高风险个体，这些个体最终将 我们预计许多分析师会受益于更频繁的 PZQ 治疗或其他治疗方法。 预测进展，这些将单独或组合开发为基于侧向流动的检测，可以 最终开发为与 MDA 一起使用的 POCT。 是否有可用的潜在治疗方法来阻止进展，但缺乏逆转较高风险的方法 一旦建立门静脉周围纤维化等级，以及解决门静脉高压的次优干预措施 其高死亡率使其成为理想的纵向筛选目标。 预测进展至不可逆等级的风险是成功执行这些措施的关键第一步。 目标还将建设 RITM 的研究能力，并通过以下方式为相关研究提供绝佳的机会： TMRC“机会基金”以及未来的赠款，用于评估个人的不同治疗策略 通过明确的随机对照试验确定纤维化进展的风险。