Novel animal models to study miRNA-mediated alcoholic liver disease

项目总结 本申请是对《酒精性肝炎临床与转化性》资助机会的回应 网络-UH2/UH3资助机制下的基础和临床前研究(RFA-AA-18-006)“。这个 我们的应用目标是激励创新的基础/临床前研究，以促进我们的 对miR-21在急性胰腺炎中作用的认识。我们提出了一种探索性而又新颖的方法来生成 肝脏靶向细胞型特异性miR-21的动物模型。作为概念证明，以支持我们的 方法，我们已经获得了肝细胞特异性miR-21-/-小鼠。使用功能损失方法， 我们首次发现miR-21与脂质代谢之间的联系，肝细胞miR-21- 21-/-小鼠在酒精喂养后对肝脏脂肪变性更敏感。作为UH2阶段的一部分(1年 和2)，我们将进一步探索miR-21-/-小鼠肝细胞对酒精反应的表型 并建议通过以下方法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 资金机制，我们在UH2阶段提出的建议将导致发展的突破 特别针对miR-21的动物模型可能对AH领域产生重大影响。这个 UH2阶段研究的成功将引导我们进入UH3验证阶段，以进一步探索 MiR-21在急性呼吸窘迫综合征(3-5岁)中作用的深入机制研究及翻译理解 通过将我们的数据整合到以患者为导向的AH网络研究中来研究基本分子机制 进一步确定miR-21在急性肝炎(4-5岁)患者中的预后意义。

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).