A PRECLINICAL MODEL OF ALCOHOLIC HEPATITIS

酒精性肝炎的临床前模型

基本信息

批准号：
10459568
负责人：
ARUN J SANYAL
金额：
$ 33.13万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
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：
2018-09-25 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459568
关键词：
Acceleration Alcohol Phenotype Alcohol consumption Alcohol withdrawal syndrome Alcoholic Hepatitis Alcoholic steatohepatitis Alcohols Animal Model Bilirubin Chronic Data Development Diet Disease Disease Progression Disease regression Dose Epigenetic Process Fibrosis Funding Mechanisms Generations Genes Genetic Drift Goals High Fat Diet Histology Human Inbreeding Individual Insulin Resistance Knowledge Liver Malnutrition Modeling Morbidity - disease rate Mouse Strains Mus Mutation National Institute on Alcohol Abuse and Alcoholism Non-Insulin-Dependent Diabetes Mellitus Obesity Parents Pathway interactions Patients Pattern Phase Pre-Clinical Model Predisposition Process Protocols documentation Public Health Reagent Research Personnel Role Safety Sampling Severities Signal Pathway Signal Transduction Site Steatohepatitis Supervision Testing Therapeutic Thinness Translating Validation alcohol effect alcohol exposure base clinically significant dietary manipulation drug testing druggable target feeding high reward high risk human data insight liver function liver injury metabolome microbiome microbiome analysis mortality mouse model mutant non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel obesogenic offspring prevent response therapeutic development therapeutic target transcriptome

项目摘要

Alcoholic Steatohepatitis (ASH) is a major cause of liver related mortality. Despite its public health significance, there has been limited therapeutic advances for ASH. A principal barrier to acceleration of therapeutics is the availability of a robust preclinical model of ASH which recapitulates human ASH. Such models are needed to better understand the role of specific genes and pathways in human ASH e.g. the PNPLA3 mutation which is associated with severe ASH and test promising compounds for both efficacy and safety. In this UH2/UH3 application, we propose to provide “proof of concept” that our recently validated diet-induced animal model of NAFLD (DIAMOND) can be leveraged as a model of ASH with specific alcohol feeding protocols and will test the following novel hypothesis: an inbred isogenic crossed C57Bl/6J and 129S1/SvlmJ (B6/S129) mouse strain will develop steatohepatitis that recapitulates the key features of human ASH with alcohol feeding. Furthermore, liver-specific expression of the human mutant I148M PNPLA3 in this mouse will accelerate the development of ASH upon alcohol feeding. As per RFA AA-18-006, the studies will be performed in two phases: UH2 Phase (yrs. 01-02): To demonstrate that alcohol feeding causes steatohepatitis resembling human ASH with respect to histology, markers of liver injury and function, and activation of signaling pathways in an isogenic strain of B6/S129 mice. Alcohol feeding will be done along with chow- or an obesogenic-diet. We will test the effect of the NIAAA alcohol model feeding strategy (to be performed at NIAAA under supervision by Dr. Gao) and an alternate strategy where we will perform single ascending dose (SAD) and multiple ascending dose (MAD) studies that will provide optimized alcohol feeding strategies including amounts given chronically along with binges to allow a phenotype of ASH to develop. We will also test the ability to accelerate development of ASH by liver-specific expression of the human I148M PNPLA3 mutant gene. These data are based on preliminary data indicating that NASH can be accelerated by this maneuver. A minimal requirement for development of ASH (steatohepatitis, increased AST and bilirubin) will be needed to proceed to the UH3 phase. UH3 Phase (yrs. 03-05): To further validate the model, define the course of disease progression and regression by modulation of alcohol intake, and the impact of ASH on the susceptibility to ASH in subsequent generations. The transcriptome, metabolome and microbiome of the model will be related to human data from the AlcHepNet consortium. Also, the effects of alcohol withdrawal after varying durations of exposure will be tested to define the “off-response”. We will also perform studies to determine the susceptibility of offspring of mice that have been allowed to develop ASH and then recover by withdrawing alcohol. Microbiome analyses will be done at the UCSD site of AlcHepNet. The investigators have the required expertise in ASH and mouse models of NASH and ASH. Together the studies will have a high impact by providing a mouse model of ASH. The project also meets the high-risk high reward criteria for the UH2/UH3 funding mechanism.

酒精性脂肪性肝炎 (ASH) 是肝脏相关死亡的一个主要原因，尽管它具有公共卫生意义。 ASH 的治疗进展有限，加速治疗的一个主要障碍是需要建立一个能够概括人类 ASH 的稳健临床前模型。更好地了解特定基因和通路在人类 ASH 中的作用，例如 PNPLA3 突变与严重的 ASH 相关，并在此 UH2/UH3 中测试有前景的化合物的有效性和安全性。应用程序中，我们建议提供“概念证明”，即我们最近验证的饮食诱导动物模型 NAFLD (DIAMOND) 可用作具有特定酒精喂养方案的 ASH 模型，并将测试以下新假设：近交同基因杂交 C57Bl/6J 和 129S1/SvlmJ (B6/S129) 小鼠品系会发展为脂肪性肝炎，这概括了人类饮酒后 ASH 的主要特征。人类突变体 I148M PNPLA3 在该小鼠中的肝脏特异性表达将加速根据 RFA AA-18-006，研究将分两个阶段进行： UH2 阶段（01-02 年）：证明饮酒会导致脂肪肝炎重新组装人类 ASH 组织学、肝损伤和功能标志物以及同基因菌株中信号通路的激活 B6/S129 小鼠将与食物或致肥胖饮食一起进行酒精喂养。 NIAAA 酒精模型喂养策略（将在高博士的监督下在 NIAAA 进行）和我们将执行单次递增剂量 (SAD) 和多次递增剂量 (MAD) 的替代策略研究将提供优化的酒精喂养策略，包括长期给予的量我们还将测试加速 ASH 发展的能力。通过人类 I148M PNPLA3 突变基因的肝脏特异性表达这些数据基于初步数据。表明这种策略可以加速 NASH 的发展 ASH 的最低要求。（脂肪性肝炎、AST 和胆红素升高）需要进入 UH3 阶段（年）。 03-05）：为了进一步验证模型，通过调节来定义疾病进展和消退的过程酒精摄入量，以及 ASH 对后代 ASH 易感性的影响。该模型的转录组、代谢组和微生物组将与来自 AlcHepNet 的人类数据相关此外，还将测试不同时间暴露后酒精戒断的影响，以确定酒精戒断的影响。我们还将进行研究以确定患有这种疾病的小鼠后代的易感性。被允许出现 ASH，然后通过戒酒恢复，微生物组分析将在 UCSD 网站 AlcHepNet 研究人员拥有 ASH 和 NASH 小鼠模型所需的专业知识。和 ASH 一起，该项目还将通过提供 ASH 小鼠模型产生巨大影响。符合UH2/UH3资助机制的高风险高回报标准。