FGFR Signaling in Liver Injury and Fibrosis

肝损伤和纤维化中的 FGFR 信号传导

• 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
• 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

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 肝纤维化是全球死亡率的重要原因。诸如慢性肝之类的因素 损伤，感染，代谢和毒素侮辱以及遗传因素与 肝纤维化的发展。快速膨胀肝内胆道上皮或导肌反应 与密切相关的高度侵入性桥接纤维化是特征的特征 晚期肝纤维化，没有明确的治疗。纤维化导致大量失真 肝功能，发展为肝衰竭。因此，预防纤维化进展是 最重要的重要性。即使经过肝脏地区的巨大科学进步 纤维化，纤维化如何发展到终末期的分子和细胞机制 疾病仍然是医学上的谜。以前我们已经表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的胆道种群 前体和纤维化细胞与活化的TGFβ共同表达促进蛋白1（PROM1） 纤维化肝中的信号传导。根据文献和初步研究，我们假设 通过与TGFβ途径的串扰，FGFR促进了导管反应和纤维化 长期受伤的肝脏。该应用的目标是阐明细胞类型特定的角色 在慢性肝损伤的环境中，导管反应和纤维化进展中的FGFR的。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信号的机制 表达细胞促进导管反应和纤维化。 （3）确定机制和 FGFR-TGFβ串扰在肝纤维化中的重要性。成功完成拟议的 工作可以确定新的治疗靶标和FGFR介导的信号传导串扰，以促进 慢性肝损伤期间的肝纤维化进展。