FGFR Signaling in Liver Injury and Fibrosis

肝损伤和纤维化中的 FGFR 信号传导

基本信息

批准号：
10521744
负责人：
Nirmala Mavila
金额：
$ 43.81万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521744
关键词：
Adult Affect Area Biliary Biliary Atresia Biology Cells Characteristics Child Cirrhosis Complication Data Disease Early Intervention Economic Burden Epithelial Epithelial Cells Event Experimental Models FGF2 gene FGFR1 gene Fibroblast Growth Factor Fibroblast Growth Factor Receptor 1 Fibroblast Growth Factor Receptors Fibrosis Focal Adhesion Kinase 1 GPC3 gene Genetic Genomics Goals Hepatic Hepatic Stellate Cell Homeostasis Human Infant Infection Injury Integral Membrane Protein Life Ligands Literature Liver Liver Failure Liver Fibrosis Mediating Medical Medical Economics Metabolic Modeling Molecular Nature Organoids Pathway interactions Population Population Heterogeneity Prevention Primary biliary cirrhosis Proteomics Publishing Reaction Receptor Activation Receptor Signaling Research Role Signal Pathway Signal Transduction Testing Toxin Transforming Growth Factor beta Transforming Growth Factors Work base cell type chronic liver disease chronic liver injury dosage end stage liver disease growth factor receptor-bound protein 2 heparin proteoglycan in vivo Model intrahepatic liver development liver injury mortality mouse model new therapeutic target novel novel strategies prevent primary sclerosing cholangitis progenitor prominin receptor receptor binding receptor-mediated signaling therapeutic target

项目摘要

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.

抽象的肝纤维化是全世界死亡的重要原因。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。肝内胆管上皮快速扩张或胆管反应与高度侵袭性桥接纤维化密切相关的是晚期肝纤维化，尚无明确治愈方法。纤维化导致显着扭曲肝功能下降，进展为肝功能衰竭。因此，预防纤维化进展至关重要至关重要。即使肝脏领域取得了巨大的科学进步纤维化，纤维化如何进展至终末期肝脏的分子和细胞机制疾病仍然是一个医学谜。之前我们已经证明成纤维细胞生长因子受体（FGFR）被高度诱导并共定位于异质胆道群体共表达 Prominin1 (PROM1) 和激活的 TGF beta 的前体细胞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 FGFR 通过与 TGF β 通路的串扰促进导管反应和纤维化慢性损伤的肝脏。该应用的目标是阐明细胞类型特异性的作用 FGFR 在慢性肝损伤背景下的导管反应和纤维化进展中的作用。具体的该提案的目的是：（1）确定 FGFR 激活的机制及其在肝损伤和纤维化。 (2) 阐明Prom1中FGFR信号传导的机制表达细胞促进导管反应和纤维化。 (3) 识别机制和 FGFR-TGFβ串扰在肝纤维化中的意义。顺利完成拟议的工作可能会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期间的肝纤维化进展。