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: 10632049
• 负责人: JENNIFER F FRIEDMAN
• 金额: $ 61.89万
• 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/10632049
• 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; Compensation; Country; Deposition; Development; Diagnostic tests; Early identification; Early treatment; Esophageal Varix; Evaluation; Exclusion; 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; biomarker identification; chemotherapy; egg; equipment acquisition; high risk; high risk population; inhibitor; intrahepatic; low and middle-income countries; manufacturing capabilities; mortality; novel marker; point of care testing; progression risk; recruit; research clinical testing; response; risk mitigation; risk prediction; screening; specific biomarkers; surgical risk; synthetic polymer Bioplex; treatment strategy; ultrasound; Address; Age; Animal Model; Antigens; Area; Area Under Curve; Biological Assay; Biological Markers; Blood specimen; Case Fatality Rates; Cessation of life; Cicatrix; Compensation; Country; Deposition; Development; Diagnostic tests; Early identification; Early treatment; Esophageal Varix; Evaluation; Exclusion; 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; biomarker identification; chemotherapy; egg; equipment acquisition; high risk; high risk population; inhibitor; intrahepatic; low and middle-income countries; manufacturing capabilities; mortality; novel marker; point of care testing; progression risk; recruit; research clinical testing; response; risk mitigation; risk prediction; 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.

项目摘要 这个热带医学研究中心（TMRC）的总体目标是为研究所研究所提出的 菲律宾的热带医学（RITM）是a）执行这项研究的关键科学目的，b）建造 RITM的研究能力，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“机会资金”和其他计划合作，TMRC在所有方面 目前，使用Praziquantel（PZQ）的预防化疗策略是治疗的主要手段 血吸虫病，“大众药物管理”（MDA）每年或两年一次交付。主要原因 严重的发病率和因肠道血吸虫病引起的死亡是继发于羊角内卵的门户纤维化 导致门静脉高血压和食管静脉曲张的沉积，出血风险很高。 重要的是，目前尚无建议识别和更积极地对待个人 在包括菲律宾在内的大多数地区，肝纤维化，让个人不经常接受（如果有） 治疗。目前，关于发展到高级门户纤维化的危险因素知之甚少， 包括生物标志物以识别风险。这是通过更频率减轻这种风险的失去机会 治疗，如果早日鉴定出来，则已显示会停止甚至逆转纤维化。我们的团体有 开发了一个多路复用的“ FibroPlex_V2”测定法，该测定现在捕获38个关键分析物 或退化。我们将采用此方法来解决研究的科学目标： 1）评估将识别出与肝链球菌链球菌肝纤维化的个体的生物标志物作为诊断 通过基线的超声（美国）以及鉴定从轻度中度发展的风险的生物标志物 我们每年评估三年的较高成绩 2）开发诊断测试以促进对现场的高风险个人的识别 通过PZQ或其他治疗方法更频繁地治疗。我们希望许多分析物将会 预测进展，这些将单独开发或将其组合为基于侧流的测定法 最终被开发为与MDA一起使用的POCT。 潜在的治疗方法停止进展的可用性，缺乏逆转更高的方法 一旦建立，等级周围纤维化，以及针对门户高血压的次优干预措施 并且其高死亡率一旦建立，它使其成为理想的筛查目标。纵向生物标志物 预测发展为较低可逆成绩的风险是至关重要的第一步。这些成功执行 AIMS还将在RITM建立研究能力，并通过 TMRC“机会资金”以及未来赠款，以评估个人的不同治疗策略 通过确定的随机对照试验的纤维化进展风险。