TREAT-VCU

描述（由申请人提供）：根据RFA-AA-12-007，“转化研究和不断发展的酒精性肝炎治疗”（TREAT）联盟成立。该联盟由印第安纳大学（IU）、梅奥诊所（MC）和弗吉尼亚联邦大学（VCU）组成。TREAT联盟的主要目标是与酒精性肝炎（AH）的基础科学家密切合作，开展面向患者的研究，并加快新发现的转化。TREAT联盟的三个主要目标是：(1)开展一项前瞻性、多中心观察性研究，建立一个具有良好特征的注册表和生物样本库，并对AH的自然史有新的认识；(2)开展三个2a期“概念验证”试验，使用三种针对AH的假定机制的新药物；(3)更好地了解人类AH的病理生理机制，并利用在特定目的1和2下收集的样本预测治疗反应。所有中心将为具体目标1作出贡献。TREAT-VCU将侧重于肠道完整性，内毒素血症，肠道微生物群，代谢组学和类二十烷类化合物特别是脂氧合酶的作用。特异性目标2提出了Imm 124-E（富含IgG抗脂多糖（LPS）的牛初乳）在严重AH患者中的2a期“概念验证”安慰剂对照，剂量范围研究。患有严重AH的受试者将接受标准治疗，并在必要时使用类固醇。受试者在开始使用类固醇时将随机接受研究药物或安慰剂。受试者将被监测治疗的成功和失败、安全性、耐受性和研究药物的有效性。TREAT-VCU的具体目的是确定脂氧合酶（LOX）的全身激活在AH严重程度的驱动因素中的作用。我们将验证肠道微生物衍生代谢物激活循环巨噬细胞产生促炎LOX的假设，该LOX激活驱动严重AH表型的途径。我们将对微生物组-宏基因组和系统性类二十烷谱进行详细表征，并使用“系统生物学”方法在严重AH、轻度AH、无AH的重度饮酒者和匹配的非酒精对照中进一步建立它们与肝脏转录组的关系。拟议的研究预计将展示对AH自然历史的新见解，作为概念证明的新疗法，并确定干预和药物开发的新靶点，从而更接近加速新发现转化的目标，直接符合NIAAA的优先事项。

DESCRIPTION (provided by applicant): The "Translational Research and Evolving Alcoholic-hepatitis Treatment" (TREAT) consortium was established in response to the RFA-AA-12-007. This consortium comprises of Indiana University (IU), Mayo Clinic (MC) and the Virginia Commonwealth University (VCU). The main objective of TREAT consortium is to perform patient oriented research in close collaboration with basic scientists in alcoholic hepatitis (AH) and expedite the translation of emerging findings. The three overarching aims of TREAT consortium are: (1) to perform a prospective, multicenter observational study leading to a well characterized registry and bio-sample repository together with newer insights into the natural history of AH~ (2) to perform three phase 2a "proof of concept" trials with three novel agents targeting putative mechanisms of AH, and (3) to better understand the mechanisms involved in the pathophysiology of human AH and predictors of response to therapy utilizing samples collected under specific aims 1 and 2. All centers will contribute for specific aim 1. The TREAT-VCU will focus on the role of gut integrity, endotoxemia, gut microbiota, metabolomics and role of eicosanoids specifically lipoxygenases. Specific aim 2 proposes a phase 2a "proof of concept" placebo- controlled, dose-ranging study of Imm 124-E (bovine colostrum enriched with IgG anti-lipopolysaccharide (LPS)) in subjects with severe AH. Subjects with severe AH will receive standard of care and steroids when indicated. The subjects when starting steroids will be randomized to receive the study drug or placebo. The subjects will be monitored to treatment success and failure, safety, tolerability and efficacy of the study drug. The specific aim 3 of TREAT-VCU is to define the role of systemic activation of lipoxygenases (LOX) as a driver of the severity of AH. We will test the hypothesis that intestinal microbiome-derived metabolites activate circulating macrophages to produce pro-inflammatory LOX that activate pathways that drive the phenotype of severe AH. We will perform detailed characterization of the microbiome-metagenome and the systemic eicosanoid profile and further establish their relationship to the hepatic transcriptome using a "systems biology" approach in subjects with severe AH, mild AH, heavy drinkers without AH and matched non-alcoholic controls. The proposed studies are expected to demonstrate new insights into the natural history of AH, novel therapies as proof of concept and identify newer targets for intervention and drug development moving closer to the goal of accelerating the translation of newer findings in direct alignment with the priorities of NIAAA.