Novel animal models to study miRNA-mediated alcoholic liver disease

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。

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).