TREAT-VCU

描述（由申请方提供）：根据RFA-AA-12-007建立了“转化研究和不断发展的酒精性肝炎治疗”（TREAT）联盟。该联盟由印第安纳州大学（IU）、马约诊所（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，进行以患者为导向的研究，并加快新发现的翻译。 TREAT联盟的三个首要目标是：（1）开展前瞻性、多中心的观察性研究，建立一个良好的登记和生物样本库，并对AH的自然史有新的认识。（2）开展三项针对AH可能机制的新药的2a期“概念验证”试验，和（3）利用根据特定目标1和2收集的样本，更好地了解人类AH的病理生理学机制和治疗反应的预测因素。所有中心都将为具体目标1做出贡献。 该中心将重点研究肠道完整性，内毒素血症，肠道微生物群，代谢组学和类花生酸特别是脂氧合酶的作用。具体目标2提出了在重度AH受试者中进行Imm 124-E（富含IgG抗脂多糖（LPS）的牛初乳）的2a期“概念验证”安慰剂对照、剂量范围研究。重度AH受试者将接受标准治疗和类固醇（如有指征）。开始类固醇治疗的受试者将随机接受研究药物或安慰剂。将监测受试者的治疗成功和失败、研究药物的安全性、耐受性和疗效。 EST-VCU的具体目标3是确定脂氧合酶（LOX）的全身激活作为AH严重程度驱动因素的作用。我们将检验以下假设：肠道微生物组衍生的代谢物激活循环巨噬细胞以产生促炎LOX，促炎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花生酸谱进行详细表征，并使用“系统生物学”方法在重度AH、轻度AH、重度饮酒者（无AH）和匹配的非酒精对照受试者中进一步建立其与肝脏转录组的关系。 拟议的研究预计将展示对AH自然史的新见解，作为概念证明的新疗法，并确定新的干预目标和药物开发，更接近加速与NIAAA优先事项直接一致的新发现转化的目标。 公共卫生相关性：“转化研究和不断发展的酒精性肝炎治疗”（TREAT）联盟由印第安纳州大学（IU）、马约诊所（MC）和弗吉尼亚联邦大学（VCU）组成。其主要目标是与酒精性肝炎（AH）的基础科学家密切合作，进行以患者为导向的研究，并迅速将新的发现转化为临床实践。该应用程序与国家酒精滥用和酒精中毒研究所（NIAAA）的战略计划直接一致。

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. PUBLIC HEALTH RELEVANCE: The "Translational Research and Evolving Alcoholic-hepatitis Treatment" (TREAT) consortium comprises of Indiana University (IU), Mayo Clinic (MC) and the Virginia Commonwealth University (VCU). The main objective is to perform patient oriented research in close collaboration with basic scientists in alcoholic hepatitis (AH) and translate newer findings into clinical practice expeditiously. This application is directly aligned with the strategic plan of National Institute of Alcohol Abuse and Alcoholism (NIAAA).