Fibrosin: A Candidate Biomarker of Schistosomal Liver Fibrosis in Humans

描述（由申请人提供）：血吸虫病由雌雄异株吸虫（扁形虫）的三种主要物种引起，目前感染了超过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]。虽然血吸虫病是有效的治疗吡喹酮（PZQ），快速再感染反弹的发病率和纤维化排除了有效的控制基础上单独化疗。 我们的R 03申请的重新提交旨在开发纤维蛋白酶的定量免疫测定，并将其应用于已经从日本血吸虫感染患者（n=616）的纵向队列研究中收集并获得的流行病学良好表征的血清。主要目的是确定血清纤维蛋白酶浓度是否与并发肝纤维化相关，以及基线血清纤维蛋白酶水平是否可预测PZQ治疗后一年的肝纤维化。这项工作是第一个翻译到人类研究的广泛相关研究的S。曼氏菌感染的小鼠，导致纤维蛋白酶的发现及其在肝纤维化中的明显作用。根据我们发表的对感染小鼠的观察（以及对S.曼氏菌感染的患者，）我们预计，感染S。与未感染的对照组相比，日本血吸虫感染者将具有显著升高的血清纤维蛋白酶浓度，并且具有超声可证实的肝纤维化的那些将具有最高水平。此外，我们预计，从S。在PZQ后4周，在一年随访时发展纤维化的患者中，与在一年随访评估时未发展纤维化的患者中的水平相比，日本血吸虫感染个体的PZQ后4周的水平将显著更高。对于有发生纤维化风险的患者，这种生物标志物有可能深刻影响疾病管理。具体来说，纤维蛋白酶的快速诊断测试（RDT）可以识别那些有肝纤维化风险的个体，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.