TREAT-Mayo

描述(由申请人提供)：由于缺乏有效的治疗方法，AH(AH)是导致发病率和死亡率的主要原因。如RFA-AA-12-007中所述，翻译 需要研究与AH相关的新机制和合适的药理药物。这项申请是组成一个联盟(转化性研究和进化酒精性肝炎治疗；治疗)的三个联盟之一，包括印第安纳大学、弗吉尼亚联邦大学和梅奥诊所。治疗联盟的总体目标是进行以患者为导向的翻译研究，以发现和测试治疗AH的新的药理学相关靶点。这一特定的Treat-Mayo应用将集中于最近的研究，这些研究揭示了caspase依赖的细胞死亡途径作为AH的致病罪魁祸首的关键作用。在这项提案中，我们将通过抑制肝细胞凋亡和无菌坏死的机制来检验中央假设，即新型caspase抑制剂emricasan在AH患者中安全有效。我们还将支持治疗联盟更广泛的目标，通过招募患者进行良好注释的登记，并为与肝脏损伤、炎症和细胞死亡广泛相关的人血清和肝组织分析提供机械性资源。因此，这一应用的具体目的是：1)建立急性肝炎患者的纵向观察队列。我们将开发一个具有良好特征的AH患者和合适的对照患者的预期多中心登记，作为进行人类治疗性(如目标2所述)和新机制(如目标3所述)研究的临床和生物样本基础。2)验证美利康治疗4周可提高急性肝炎患者存活率的假设。我们将进行一项早期的随机、双盲、安慰剂对照研究，纳入一组特殊人群的重度急性肝炎患者，这些患者不适合根据特定的禁忌症接受皮质类固醇治疗。3)验证细胞凋亡和无菌坏死参与AH发病的假说，认为细胞凋亡和无菌坏死是Emricasan的致病靶点。我们将检测血清和肝组织中的凋亡和无菌坏死标记物，以了解这些分子过程是如何在人类AH中促进肝脏损伤和炎症的。因此，这项由一组在急性肝炎和基础肝损伤方面有丰富临床经验的研究人员提交的研究报告，将确定一种新的创新疗法--caspase抑制剂emricasan在急性肝炎患者中的安全性和潜在疗效。此外，拟议的机制分析将阐明不同的细胞死亡途径如何在人类AH中起作用，以及Caspase抑制如何取消这些途径，从而抑制AH患者的肝脏损伤和炎症。我们在患者招募试验方面的记录和肝脏损伤途径方面的丰富资源也将为该联盟的更广泛成功提供关键组成部分。总而言之，这项应用将为我们推进对AH破坏性条件的理解迈出重要的一步。

DESCRIPTION (provided by applicant): AH (AH) is a major cause of morbidity and mortality due to a lack of effective treatments for this condition. As stated in RFA-AA-12-007, translational investigations are needed on new mechanisms and suitable pharmacological agents relevant to AH. This application is one of three that comprise a consortium (Translational Research and Evolving Alcoholic Hepatitis Treatment; TREAT) and include Indiana University, Virginia Commonwealth University, and Mayo Clinic. The Overall goals of the TREAT consortium are to perform patient oriented translational studies that will uncover and test new pharmacologically relevant targets for the treatment of AH. This specific TREAT-Mayo application will focus on expansion of recent studies that have revealed a key role for caspase dependent cell death pathways as a pathogenic culprit in AH. In this proposal, we will test the Central Hypothesis that the novel caspase inhibitor emricasan is safe and effective in patients with AH through a mechanism involving inhibition of hepatocellular apoptosis and sterile necrosis. We will also support the broader goals of the TREAT consortium by recruiting patients for a well annotated registry and by providing a mechanistic resource for human serum and liver tissue analyses that are broadly pertinent to liver injury, inflammation, and cell death. Thus, the Specific Aims of thi application are to: 1) Develop longitudinal observational cohort of patients with AH. We will develop a prospective multicenter registry of patients with well characterized AH and suitable controls that serves as the clinical and biosample based foundation for conducting human therapeutic (as described in Aim 2) and novel mechanistic (as described in Aim 3) studies. 2) Test the hypothesis that 4-week emricasan administration will improve survival in patients with AH. We will conduct an early phase randomized, blinded, placebo controlled study, which will include a special population of patients with severe AH who are not otherwise candidates for corticosteroid therapy based on specific contraindications. 3) Test the hypothesis that apoptosis and sterile necrosis contribute to development of AH and are pathogenic targets of emricasan. We will measure serum and liver tissue markers of both apoptosis and sterile necrosis to inform our understanding of how these molecular processes contribute to liver injury and inflammation in human AH. Thus, this study, submitted by a group of investigators with extensive experience in clinical AH and basic liver injury, will determine the safety and potential efficacy of a novel and innovative therapy, the caspase inhibitor emricasan, in patients with AH. Additionally, the proposed mechanistic analyses will elucidate how distinct cell death pathways contribute to human AH and how caspase inhibition abrogates these pathways thereby inhibiting liver injury and inflammation in patients with AH. Our track record in patient recruitment trials and expansive resources in liver injury pathways will also provide key components for the broader success of this consortium. In total, this application will provide a major step in advancing our understanding of the devastating condition of AH.