Fibrosin: A Candidate Biomarker of Schistosomal Liver Fibrosis in Humans

描述(申请人提供)：血吸虫病由三种主要的雌雄异体吸虫(扁虫)引起，目前感染超过2.5亿人，估计导致2%-15%的慢性残疾，并导致流行地区的健康状况不佳和经济停滞[1]。虽然吡喹酮(PZQ)可以有效地治疗血吸虫病，但快速的再感染和反跳的发病率和纤维化阻碍了仅基于化疗的有效控制。我们R03申请的重新提交旨在开发一种纤维蛋白的定量免疫分析方法，并将其应用于已经从日本血吸虫感染患者的纵向队列研究(n=616)中收集和获得的流行病学特征良好的血清。主要目的是确定血清纤维蛋白浓度是否与并发肝纤维化有关，以及基线血清纤维蛋白水平是否预测PZQ治疗一年后的肝纤维化。这项工作是对感染曼氏葡萄球菌的小鼠的广泛相关研究的第一次人类研究，这些研究导致了纤维蛋白的发现及其在肝纤维化形成中的明显作用。根据我们在感染小鼠(以及对曼氏血吸虫感染患者的小型初步研究)中发表的观察结果，我们预计，与未感染的对照组相比，感染日本血吸虫的患者的血清纤维蛋白浓度将显著升高，而超声可证实的肝纤维化患者的血清纤维蛋白水平将最高。此外，我们预计，在PZQ治疗后4周从日本血吸虫感染者身上采集的血清中的纤维蛋白水平，在一年后发生纤维化的患者中将显著高于在一年随访评估中未出现纤维化的患者。对于有发生纤维化风险的患者来说，这种生物标记物有可能深刻地影响疾病管理。具体地说，纤维蛋白的快速诊断试验(RDT)可以确定那些有肝纤维化风险的人，并优先考虑更频繁的PZQ治疗。

DESCRIPTION (provided by applicant): Schistosomiasis, caused by three principle species of dioecious trematodes (flatworms), currently infects over 250 million individuals, results in an estimated 2-15% chronic disability, and contributes to poor health and economic stagnation in endemic areas [1]. Although schistosomiasis is effectively treated with praziquantel (PZQ), rapid reinfection with rebound morbidity and fibrosis precludes effective control based on chemotherapy alone. The resubmission of our R03 application seeks to develop a quantitative immunoassay for fibrosin and apply it to epidemiologically well-characterized sera already collected and available from a longitudinal cohort study of Schistosoma japonicum-infected patients (n=616). The principle goal is to determine whether serum fibrosin concentrations are associated with concurrent hepatic fibrosis and whether baseline serum fibrosin levels predict hepatic fibrosis one year post-PZQ treatment. The work serves as the first translation to human research of extensive related studies of S. mansoni-infected mice that led to the discovery of fibrosin and its apparent role in hepatic fibrogenesis. Based on our published observations in infected mice (and in a small preliminary study of S. mansoni-infected patients,) we anticipate that patients infected with S. japonicum will have significantly elevated serum fibrosin concentrations compared to uninfected controls, and that those with ultrsonographically-demonstrable liver fibrosis will have the highest levels. Furthermore, we anticipate that fibrosin levels measured in serum collected from S. japonicum infected individuals 4 weeks post-PZQ will be significantly higher in patients who develop fibrosis at one yr of follow-up compared to levels in patients who do not develop fibrosis at a one-year follow-up assessment. Such a biomarker for patients at risk of developing fibrosis has the potential to profoundly influence disease management. Specifically, a rapid diagnostic test (RDT) for fibrosin could identify those individuals at risk of hepatic fibrosis and prioritize them from more frequent PZQ treatment.