FGFR Signaling in Liver Injury and Fibrosis

摘要 肝纤维化是世界范围内死亡的重要原因。慢性肝病等因素 损伤、感染、代谢和毒素损伤以及遗传因素与 肝纤维化的发展。快速扩张的肝内胆管上皮或小管反应 与高度侵袭性桥接性纤维化密切相关， 晚期肝纤维化，目前尚无确切的治愈方法。纤维化导致了一个显着的扭曲， 肝功能，进展为肝功能衰竭。因此，预防纤维化进展是有效的。 至关重要即使在肝脏领域取得了巨大的科学进步之后， 纤维化，纤维化如何进展到终末期肝脏的分子和细胞机制 疾病仍然是医学上的一个谜。以前我们已经证明成纤维细胞生长因子 受体（FGFRs）高度诱导和共定位于一个异质群体的胆汁 共表达Prominin 1（PROM 1）和活化TGF β的前体和促纤维化细胞 纤维化肝脏中的信号传导。根据文献和初步研究，我们假设， FGFRs通过其与TGF β通路的相互作用促进了肾小管反应和纤维化， 慢性损伤的肝脏本申请的目的是阐明细胞类型特异性作用 FGFRs在慢性肝损伤的小管反应和纤维化进展中的作用。具体 本研究的主要目的是：（1）明确FGFRs的激活机制及其在肿瘤治疗中的意义。 肝损伤和纤维化。(2)阐明Prom 1中FGFR信号传导的机制 表达细胞促进小管反应和纤维化。(3)确定机制和 FGFR-TGF β串扰在肝纤维化中意义圆满完成拟议的 这项工作可以确定新的治疗靶点和FGFR介导的信号串扰， 慢性肝损伤时肝纤维化进展。

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.