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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.

摘要