Fibrosin: A Candidate Biomarker of Schistosomal Liver Fibrosis in Humans

描述（由申请人提供）：血吸虫病由三种主要的雌雄异株吸虫（扁虫）引起，目前感染超过2.5亿人，估计造成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。尽管吡喹酮（PZQ）能有效治疗血吸虫病，但快速再感染、反弹发病率和纤维化阻碍了单纯化疗的有效控制。重新提交的R03申请旨在开发一种纤维蛋白的定量免疫测定方法，并将其应用于从日本血吸虫感染患者（n=616）的纵向队列研究中收集的具有良好流行病学特征的血清。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治疗一年后肝纤维化。这项工作是对曼氏链球菌感染小鼠的广泛相关研究的首次转化，该研究导致了纤维蛋白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（以及对曼氏链球菌感染患者的一项小型初步研究），我们预计，与未感染的对照组相比，感染日本血吸虫的患者血清纤维蛋白浓度将显著升高，超声检查显示肝纤维化的患者血清纤维蛋白水平最高。此外，我们预计pzq后4周采集的日本血吸虫感染者血清中纤维蛋白水平在随访1年时发生纤维化的患者中显著高于随访1年时未发生纤维化的患者。这种生物标志物对于有纤维化风险的患者具有深远影响疾病管理的潜力。具体来说，纤维蛋白的快速诊断测试（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.