FGFR Signaling in Liver Injury and Fibrosis

摘要 肝纤维化是世界范围内死亡的一个重要原因。慢性肝病等因素 损伤、感染、新陈代谢和毒素侮辱以及遗传因素与 肝纤维化的发展。快速扩张的肝内胆管上皮或胆管反应 与高度侵袭性桥接性纤维化密切相关的特点是 晚期肝纤维化，目前尚无确切的治疗方法。纤维化导致严重扭曲 肝功能，进展为肝功能衰竭。因此，预防纤维化的进展是 最重要的是。即使在肝脏领域取得巨大的科学进步之后 纤维化，纤维化进展为终末期肝脏的分子和细胞机制 疾病仍然是一个医学谜团。此前我们已经证明成纤维细胞生长因子 受体(FGFRs)被高度诱导并共同定位于一个不同的胆汁种群 Prominin1(PROM1)前体细胞和前纤维化细胞共表达活化的转化生长因子β 纤维化肝脏中的信号。根据文献和初步研究，我们假设 FGFRs通过与转化生长因子β途径的串扰促进小鼠肾小管反应和纤维化 慢性损伤的肝脏。本应用程序的目标是阐明细胞类型特定的角色 FGFRs在慢性肝损伤的导管反应和纤维化进展中的作用。特定的 这项建议的目的是：(1)确定FGFRs的激活机制及其在 肝脏损伤和纤维化。(2)阐明FGFR在Prom1中的信号转导机制 表达细胞促进导管反应和纤维化。(3)确定机制和 FGFR-转化生长因子β信号在肝纤维化中的意义圆满完成拟议中的 工作可能确定新的治疗靶点和FGFR介导的信号串扰，从而促进 慢性肝损伤过程中肝纤维化的进展。

ABSTRACT Liver fibrosis is a significant cause of mortality worldwide. Factors such as chronic liver injury, infection, metabolic and toxin insults, and genetic factors are associated with the development of liver fibrosis. Rapidly expanding intrahepatic biliary epithelium or ductular reaction with a closely associated highly invasive bridging fibrosis are the characteristic features of advanced liver fibrosis, which has no definite cure. Fibrosis leads to a significant distortion of hepatic function, progresses to liver failure. Therefore, the prevention of fibrosis progression is of paramount importance. Even after tremendous scientific advancements in the area of liver fibrosis, the molecular and cellular mechanisms of how fibrosis progresses to an end-stage liver disease remain a medical enigma. Previously we have shown that Fibroblast growth factor receptors (FGFRs) were highly induced and co-localized to a heterogeneous population of biliary precursors and profibrogenic cells co-expressing Prominin1 (PROM1) with an activated TGF beta signaling in fibrotic livers. Based on the literature and preliminary studies, we hypothesize that FGFRs via its crosstalk with the TGF beta pathway promotes ductular reaction and fibrosis in chronically injured livers. The goals of this application are to elucidate the cell-type-specific role of FGFRs in ductular reaction and fibrosis progression in a setting of chronic liver injury. Specific aims of this proposal are: (1) Identify the mechanisms of FGFRs activation and its significance in liver injury and fibrosis. (2) Elucidate the mechanism by which FGFR signaling in Prom1 expressing cells promote ductular reaction and fibrosis. (3) Identify the mechanism and the significance of FGFR-TGF beta crosstalk in liver fibrosis. Successful completion of the proposed work may identify novel therapeutic targets and FGFR-mediated signaling crosstalk that promotes liver fibrosis progression during chronic liver injury.