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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：
9794130
负责人：
Suthat Liangpunsakul
金额：
$ 21.53万
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 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9794130
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).

项目摘要本申请是为了响应资助机会“酒精性肝炎临床和翻译网络-基础和临床前研究（RFA-AA-18-006），根据UH 2/UH 3资助机制”。的我们申请的目标是激励创新的基础/临床前研究，以促进我们的了解miR-21在AH中的作用。我们提出了一种探索性但新颖的方法来生成靶向肝脏中细胞类型特异性miR-21的动物模型。作为概念验证，以支持我们的通过这种方法，我们已经产生了肝细胞特异性miR-21-/-小鼠。使用功能丧失方法，我们首次发现miR-21与脂质代谢之间的联系，即肝细胞miR-21与脂质代谢之间的联系。 21-/-小鼠在酒精喂养后对肝脏脂肪变性更敏感。作为UH 2阶段的一部分（第1年和2），我们将进一步探索肝细胞miR-21-/-小鼠对酒精的反应表型喂养，并建议评估建立两个新的实验动物模型的可行性，分别产生KC特异性和HSC特异性miR-21-/-小鼠。作为这个项目的目标之一，我们在UH 2阶段的建议将导致发展的突破，这是一种专门针对miR-21的动物模型，可能对AH领域产生重大影响。的 UH 2阶段研究的成功将引导我们进入UH 3验证阶段，以进一步探索对miR-21在AH（3-5岁）中的作用进行深入的机制研究，通过将我们的数据整合到AH网络以患者为导向的研究中，进一步确定miR-21在AH患者（4-5岁）中的预后意义。