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：
10467095
负责人：
Gianfranco D Alpini
金额：
$ 56.71万
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/10467095
关键词：
3-Dimensional Address Animal Model Applications Grants Attenuated Automobile Driving Biliary Calcitonin Gene-Related Peptide Cell Aging Cell Line Cells Cholestasis Choline 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 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 Public Health Reaction Role Sampling Sensory Serum Signal Transduction System TLR4 gene Testing Therapeutic Transforming Growth Factors United States Western World antagonist autocrine base 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 macrophage 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.

项目概要非酒精性脂肪肝 (NAFLD) 是一个令人担忧的公共卫生问题，目前被认为是最严重的公共卫生问题。 NAFLD 患者可能会发展为非酒精性脂肪性肝炎。（NASH）可能会导致肝损伤，并可能进展为肝硬化。我们已经证明，激活。 α-降钙素基因相关肽 (αCGRP)/降钙素受体样受体 (CRLR) 轴的作用发挥着关键作用在动物模型中胆汁淤积期间胆道损伤诱导的胆管细胞增殖中的作用。证据和我们新的初步数据表明，胆管细胞在发病机制中发挥着关键作用 NAFLD/NASH 通过激活胆道损伤、导管反应 (DR)、衰老和随后的肝脏我们的初步数据表明，动物胆管细胞中的 αCGRP/CRLR 轴上调。 NAFLD/NASH（高脂饮食（HFD）和蛋氨酸和胆碱缺乏（MCD）肝毒性饮食）模型患有 NAFLD 和 NASH 的人类肝脏样本支持 αCGRP/CRLR 轴发挥关键作用的概念基于这些发现，我们提出了 NAFLD 和 NASH 表型的核心。假设 αCGRP/CRLR 轴信号传导对于介导 DR 和激活的促纤维化胆道至关重要触发 HSC 激活的表型，以及肝细胞中的脂肪变性，导致肝细胞的进展 NAFLD/NASH 期间的肝纤维化为了检验我们的假设，提出了两个具体目标：(i) HFD 和 MCD。肝毒性饮食诱导的 CGRP/CRLR 轴激活刺激 DR，胆道衰老引发 NAFLD/NASH 期间随后的脂肪变性和纤维化；以及 (ii) αCGRP/CRLR 轴的治疗性抑制和下游途径减弱激活的神经内分泌/促纤维化胆道表型 NAFLD/NASH 进展期间的脂肪变性和纤维化拟议的研究将在细胞中进行。特定 CRLR 敲除小鼠模型以及人 NAFLD/NASH 胆管细胞系的体外研究和 3D 类器官的 CGRP/CRLR 轴和下游通路的激活将在人类中相关。 NAFLD/NASH 样本的成功完成将提供转化机制。 CGRP/CLR 轴的激活如何在疾病进展过程中介导 DR 和肝胆纤维化我们的研究还将为 NAFLD/NASH 和其他疾病的新治疗方法提供见解。以导管反应和肝胆纤维化为特征的肝脏疾病。