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

• 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
• 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

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.

项目摘要 非酒精性脂肪肝（NAFLD）是一个令人担忧的公共卫生问题，现在被认为是最严重的疾病。 西方世界常见的肝病。NAFLD患者可能发生非酒精性脂肪性肝炎 （NASH），其中可能发生肝损伤，肝损伤可能进展为肝硬化。我们已经证明激活 α-降钙素基因相关肽（α-CGRP）/降钙素受体样受体（CRLR）轴的调节在调节降钙素基因相关肽（CGRP）/降钙素受体样受体（CRLR）的表达中起着关键作用。 在动物模型胆汁淤积期间胆汁损伤诱导的胆管细胞增殖中的作用。最近 证据和我们新的初步数据表明，胆管细胞在肝硬化的发病机制中起关键作用， NAFLD/NASH通过激活胆道损伤、胆管反应（DR）、衰老和随后的肝脏 纤维化我们的初步数据表明，在动物胆管细胞中，CGRP/CRLR轴上调， NAFLD/NASH模型（高脂饮食（HFD）和蛋氨酸和胆碱缺乏（MCD）肝毒性饮食）和 患有NAFLD和NASH的人类肝脏样本支持以下概念，即CGRP/CRLR轴在NAFLD和NASH中起关键作用， 在NAFLD和NASH表型的进展中。根据这些发现，我们提出了中央 这一假说认为，CGRP/CRLR轴信号传导对于介导DR和激活促纤维化胆管细胞至关重要， 表型，触发HSC活化，以及肝细胞中的脂肪变性，有助于肝硬化的进展。 NAFLD/NASH期间的肝纤维化。为了验证我们的假设，提出了两个具体的目标：（i）HFD和MCD 肝毒性饮食诱导的CGRP/CRLR轴的激活刺激DR，胆汁衰老触发DR， NAFLD/NASH期间的随后的脂肪变性和纤维化;和（ii）治疗性抑制NAFLD/NASH期间的CGRP/CRLR轴 和下游途径减弱激活的神经内分泌/促纤维化胆汁表型肝 在NAFLD/NASH的进展过程中的脂肪变性和纤维化。拟定研究将在细胞中进行 特异性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CGRP/CRLR轴及其下游通路的激活在人类中将是相关的， NAFLD/NASH的样本。成功完成拟议的研究将提供一个翻译机制， 研究了在糖尿病进展过程中，CGRP/CGRP轴的激活如何介导DR和肝胆纤维化。 NAFLD/NASH。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。 以胆管反应和肝胆纤维化为特征的肝脏疾病。