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: 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
• 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

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 非酒精性脂肪肝疾病（NAFLD）是一个令人震惊的公共卫生问题，现在被认为是最大的 西方世界的常见肝病。 NAFLD患者可能患有非酒精性脂肪性肝炎 （NASH）可能会发展出可能发展为肝硬化的肝损伤。我们已经表明激活 α-钙调蛋白基因相关肽（CGRP）/降钙素受体样受体（CRLR）轴的轴的轴均具有钥匙 动物模型中胆汁淤积过程中胆道损伤引起的胆管细胞增殖中的作用。最近的 证据和我们的新型初步数据表明胆管细胞在发病机理中起关键作用 NAFLD/NASH通过激活胆道损伤，导管反应（DR），敏感和随后的肝脏 纤维化。我们的初步数据表明，在动物的胆管细胞中更新了CGRP/CRLR轴 NAFLD/NASH（高脂饮食（HFD），甲硫氨酸和胆碱缺陷型（MCD）肝饮食）的模型和 带有NAFLD和NASH的人肝样品支持CGRP/CRLR轴起关键作用的概念 在NAFLD和NASH表型的进展中。根据这些发现，我们提出了中央 假设CGRP/CRLR轴信号对于介导DR和激活的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 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 肝饮食诱导的CGRP/CRLR轴的激活刺激了DR，胆道感应触发了 NAFLD/NASH期间随后的脂肪变性和纤维化； （ii）CGRP/CRLR轴的治疗抑制 下游途径减弱了活化的神经内分泌/纤维化胆道表型肝 NAFLD/NASH进展过程中的脂肪变性和纤维化。提出的研究将在细胞中进行 特定的CRLR敲除小鼠模型以及人NAFLD/NASH胆管细胞细胞系中的体外研究 和3D器官。 CGRP/CRLR轴和下游途径的激活将在人类中相关 NAFLD/NASH的样本。成功完成拟议的研究将提供转化机制 CGRP/CLR轴的激活如何介导DR和肝纤维纤维化。 nafld/nash。我们的研究还将为NAFLD/NASH和其他其他新型治疗方法提供见解 肝脏疾病的特征是导管反应和肝纤维纤维化。