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Novel animal models to study miRNA-mediated alcoholic liver disease

研究 miRNA 介导的酒精性肝病的新型动物模型

基本信息

批准号：
10228102
负责人：
Suthat Liangpunsakul
金额：
$ 38.81万
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：
2018
资助国家：
美国
起止时间：
2018-09-26 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228102
关键词：
Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols Animal Model Cirrhosis Clinical Complex Data Disease Experimental Animal Model Fatty Liver Fibrosis Functional disorder Funding Mechanisms Funding Opportunities Genes Genetic Transcription Goals Hepatic Hepatocyte Histologic Human Inflammation Kupffer Cells Lead Liver Mediating Metabolism MicroRNAs Molecular Mus National Institute on Alcohol Abuse and Alcoholism Outcome Pathogenesis Pathology Patients Phase Phenotype Process Reporting Research Design Role Secondary to Series Serum Severities Syndrome Time Tissues Translating United States Untranslated RNA Up-Regulation Validation alcohol response animal model development cell type chronic liver disease clinical application clinically significant cohort feeding human disease innovation insight lipid metabolism loss of function mortality novel novel strategies patient oriented research pre-clinical research prognostic significance response stellate cell success transcriptome

项目摘要

PROJECT SUMMARY This application is in response to the funding opportunity “Alcoholic hepatitis clinical and translational network – basic and preclinical research (RFA-AA-18-006) under UH2/UH3 funding mechanism”. The goals of our application are to stimulate innovative basic/pre-clinical research to facilitate our understanding on the role of miR-21 in AH. We propose an exploratory yet novel approach to generate animal model targeting cell-type specific miR-21 in the liver. As a proof of concept to support our approach, we have generated hepatocyte specific miR-21-/- mice. Using the loss of function approach, we found, for the first time the connection between miR-21 and lipid metabolism, that hepatocyte miR- 21-/- mice are more sensitive to hepatic steatosis after alcohol feeding. As part of UH2 phase (Yrs 1 and 2), we will further explore the phenotypes of hepatocyte miR-21-/- mice in response to alcohol feeding and also propose to assess the feasibility of creating two new experimental animal models by generating KC-specific and HSC-specific miR-21-/- mice, respectively. As one of the goals of this funding mechanism, our proposal during the UH2 phase will lead to a breakthrough in the development of animal models specifically targeting miR-21 that could have a major impact on AH field. The success of the study during the UH2 phase will lead us to the UH3 validation phase to further explore the in-depth mechanistic study on the role of miR-21 in AH (Yrs 3-5) and to translate the understanding of the basic molecular mechanism by integrating our data into the AH network patient-oriented research setting to further determine the prognostic significance of miR-21 in patients with AH (Yrs 4-5).

项目总结