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Role of Sensory Innervation in High Fat Diet-Induced Hepatotoxicity

感觉神经支配在高脂肪饮食引起的肝毒性中的作用

基本信息

批准号：
10596643
负责人：
Gianfranco D Alpini
金额：
$ 53.3万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2022-04-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596643
关键词：
3-Dimensional Address Animal Model Applications Grants Attenuated Automobile Driving Biliary Calcitonin Gene-Related Peptide Calcitonin-Gene Related Peptide Receptor Cell Aging Cell Line Cells Cholestasis Choline Deficiency Cirrhosis Correlative Study Data Development Diabetic mouse Diet Disease Progression Down-Regulation Drug Delivery Systems Epithelial Cells Fatty Liver Fibrosis Health Hepatic Stellate Cell Hepatobiliary Hepatocyte Hepatology Hepatotoxicity High Fat Diet Human Hyperglycemia In Vitro Inflammatory Intrahepatic bile duct Knock-out Knockout Mice Liver Liver Cirrhosis Liver Fibrosis Liver diseases LoxP-flanked allele Macrophage Mediating Metabolic Methionine MicroRNAs Modeling Monoclonal Antibodies Monoclonal Antibody Therapy Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Obesity Organoids Pathogenesis Pathway interactions Patients Peptide Signal Sequences Peptides Phenotype Play Proliferating Public Health Reaction Role Sampling Sensory Serum Signal Transduction System TLR4 gene Testing Therapeutic Transforming Growth Factors United States Western World antagonist autocrine bile duct calcitonin receptor-like receptor cell type cholangiocyte chronic liver disease diet-induced obesity effective therapy end stage liver disease in vivo insight knock-down liver injury mouse model mouse toll-like receptor 4 nanoparticle drug nerve supply non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention paracrine patient subsets receptor-activity-modifying protein senescence targeted delivery

项目摘要

Project Summary Nonalcoholic fatty liver disease (NAFLD) is an alarming public health concern and now considered the most common liver disease in the Western world. Patients with NAFLD may develop nonalcoholic steatohepatitis (NASH) of which may develop hepatic injury that may progress to liver cirrhosis. We have shown that activation of the alpha-calcitonin gene-related peptide (CGRP)/Calcitonin receptor-like receptor (CRLR) axis plays a key role in cholangiocyte proliferation induced by biliary damage during cholestasis in animal models. Recent evidence and our novel preliminary data indicate that cholangiocytes play a key role in the pathogenesis of NAFLD/NASH through activation of biliary damage, ductular reaction (DR), senescence, and subsequent liver fibrosis. Our preliminary data showing that the CGRP/CRLR axis is upregulated in cholangiocytes in animal models of NAFLD/NASH (high-fat diet (HFD) and methionine and choline-deficient (MCD) hepatoxic diet) and human liver samples with NAFLD and NASH support the concept that the CGRP/CRLR axis plays a key role in the progression of NAFLD and NASH phenotypes. Based upon these findings, we propose the central hypothesis that the CGRP/CRLR axis signaling is critical for mediating DR and activated profibrogenic biliary phenotype that triggers HSC activation, as well as steatosis in hepatocytes contributing to the progression of hepatic fibrosis during NAFLD/NASH. To test our hypothesis, two Specific Aims are proposed: (i) HFD and MCD hepatoxic diet-induced activation of the CGRP/CRLR axis stimulates DR, biliary senescence triggering the subsequent steatosis and fibrosis during NAFLD/NASH; and (ii) Therapeutic inhibition of the CGRP/CRLR axis and downstream pathways attenuates the activated neuroendocrine/profibrogenic biliary phenotype hepatic steatosis and fibrosis during the progression of NAFLD/NASH. The proposed studies will be performed in cell specific CRLR knockout mice models as well as in vitro studies in human NAFLD/NASH cholangiocytes cell lines and 3D organoids. The activation of the CGRP/CRLR axis and downstream pathways will be correlated in human samples of NAFLD/NASH. Successful completion of the proposed studies will provide a translational mechanism of how activation of the CGRP/CLR axis mediates DR and hepatobiliary fibrosis during the progression of NAFLD/NASH. Our study will also provide insight for novel therapeutic approaches for NAFLD/NASH and other liver diseases characterized by ductular reaction and hepatobiliary fibrosis.

项目总结