Molecular Subtypes for Targeted Therapies in Alcoholic Hepatitis

描述(申请人提供)：酒精性肝炎(AH)新靶向疗法的开发是临床肝病学中较为迫切的需求之一。为了实现这一目标，需要建立大型多学科网络。拟议的“确定酒精性肝炎分子靶标的综合方法”(InTeam)将协调一个由临床医生、内科科学家、基础科学家和生物信息学专家组成的多学科小组。InTeam的主要假设是，为(AH)未来的临床试验提供有用的框架的最合理的方法包括(I)确定疾病过程的EY驱动因素，(Ii)对AH的分子图谱和亚型进行分类，以及(Iii)基于关键驱动因素和分子分类来确定“可用药”靶标。 此外，缺乏AH的小鼠模型，使得在临床前的小鼠研究中不可能以有意义的方式评估有希望的靶点。为此，InTeam将整合从人类AH分子病理学研究和动物模型关键通路功能研究中获得的数据。拟议的InTeam财团包括三个研究项目、十个临床中心、一个人类生物库和一个老鼠模型核心。人类生物库核心将从10个学术肝脏中心收集迄今最大规模的AH患者样本，并建立一个全面的数据库，作为拟议的转化性研究的基础，并成为更广泛的科学界的宝贵资产。小鼠模型核心将在建立和评估基于该联盟确定的人类AH的病理生理学和分子驱动因素的AH小鼠模型后进行小鼠研究。这三个科学项目将结合对急性肝炎患者的彻底分子特征以及对关键和有针对性的途径的研究，这些途径推动急性肝炎疾病进展和结局的关键方面，如炎症、损伤和再生。项目1(“酒精性肝炎靶向治疗的分子亚型”，PI：Ramon Bataller和Philippe Mathurin)将确定急性肝炎的分子和细胞驱动因素，使用RNA测序、运动学、代谢组学和新的系统生物学方法提供分子分类，并确定不良结果的贡献者和相关的祖细胞积累。项目2(“靶向酒精性肝炎的DAMPS”，PI：Robert Schwabe和Wajahat Mehal)将探索包括HMGB1和线粒体DAMPS在内的损害相关分子模式(DAMP)在急性肝炎时肝脏和全身炎症以及器官损害的发展中的作用。项目3(“作为酒精性肝炎的治疗靶点的微生物群”，PIS：Bernd Schnabl和David Brenner)将使用尖端焦磷酸测序和生物分析工具来调查肠道微生物组、转录组和代谢组的变化，作为治疗急性肝炎治疗干预的潜在贡献者和目标。总之，InTeam网络将提供迄今为止最大的AH患者样本系统样本和数据收集与致力于翻译性AH研究的强大科学家团队和参与临床中心的大型网络的独特组合。我们预计，该联盟的系统性方法和翻译性质将促进对AH的理解，并为其预防和治疗提供新的方法。

DESCRIPTION (provided by applicant): The development of new targeted therapies for alcoholic hepatitis (AH) is one of the more urgent needs in clinical hepatology. To reach this goal, large multidisciplinary networks are required. The proposed initiative "Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis" (InTeam) will coordinate a multidisciplinary group composed of clinicians, physician-scientists, basic scientists and bioinformatics experts. The overarching hypothesis of InTeam is that the most rational way to provide a useful framework for future clinical trials in (AH) consists of the (i) determination of ey drivers of the disease process, (ii) classification of molecular profiles and subtypes of AH, and (iii) identification of "druggable" targets based on both key drivers and molecular classification. Moreover, mouse models for AH are lacking making it impossible to evaluate promising targets in preclinical mouse studies in a meaningful manner. For this purpose, InTeam will integrate data obtained from molecular pathology studies in human AH and functional studies of key pathways in animal models. The proposed InTeam consortium includes three research projects, ten clinical centers, a Human Biorepository and a Mouse Models Core. The Human Biorepository Core will generate the to-date largest collection of samples from patients with AH from 10 academic liver centers and a comprehensive database that will serve as a basis for the proposed translational studies and be a valuable asset for the broader scientific community. The Mouse Models core will conduct murine studies after establishing and evaluating mouse models of AH based on the pathophysiology and molecular drivers of human AH determined by this consortium. The three scientific projects will combine a thorough molecular characterization of patients with AH with studies on key and targetable pathways that drive key aspects of AH disease progression and outcome such as inflammation, injury and regeneration. Project 1 ("Molecular Subtypes for Targeted Therapies in Alcoholic Hepatitis", PIs: Ramon Bataller and Philippe Mathurin) will identify molecular and cellular drivers of AH to provide a molecular classification using RNA sequencing, kinomic, metabolomic and novel systems biology approaches, and determine contributors to unfavorable outcome and the associated progenitor cell accumulation. Project 2 ("DAMPs for Targeting Alcoholic Hepatitis", PIs: Robert Schwabe and Wajahat Mehal) will explore the contribution of damage-associated molecular patterns (DAMPs) including HMGB1 and mitochondrial DAMPs, to the development of hepatic and systemic inflammation, and organ damage in AH. Project 3 ("Microbiota as Therapeutic Targets in Alcoholic Hepatitis", PIs: Bernd Schnabl and David Brenner) will using cutting-edge pyrosequencing and bioanalytical tools to investigate changes in the intestinal microbiome, metatranscriptome and metabolome as potential contributors and targets for therapeutic interventions in AH. In summary, the InTeam network will provide a unique combination of the to-date largest systematic sample and data collection of AH patient samples with a strong group of scientists dedicated to translational AH research and a large network of participating clinical centers. We anticipate that the systematic approach and translational nature of this consortium will advance the understanding of AH, and provide novel approaches for its prevention and treatment.