Novel therapies in alcoholic hepatitis University of Louisville

路易斯维尔大学酒精性肝炎的新疗法

基本信息

批准号：
9088191
负责人：
CRAIG J. MCCLAIN
金额：
$ 26.1万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088191
关键词：
Acute Alcoholic Hepatitis Adenylate Cyclase Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Amino Acids Anabolic steroids Animal Model Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Attenuated Bacteria Biological Assay Biological Markers Cessation of life Cirrhosis Clinical Clinical Trials Cyclic AMP Data Development Dinoprostone Disease Effectiveness Endotoxemia Endotoxins FDA approved Glucocorticoids Goals Hepatorenal Syndrome Human Hypoxia Hypoxia Inducible Factor In Vitro Inflammation Interleukin-1 Interleukin-10 Intestines Label Laboratories Life Literature Liver Lung Metabolism Misoprostol Morbidity - disease rate Mucins Mucous body substance Nutritional Support Patients Pentoxifylline Peptides Permeability Pharmacotherapy Phosphodiesterase Inhibitors Placebos Positioning Attribute Prednisone Probiotics Production Prognostic Marker Protocols documentation Research Research Personnel Resistance Role Sampling Severities Severity of illness Signal Transduction Site Specimen Staging Steroid Resistance Steroid therapy Steroids Stimulus Supplementation TNF gene Therapeutic Therapeutic Agents Therapeutic Intervention Translating Translational Research Treatment Efficacy Universities Zinc supplementation analog clinical practice cooperative study cytokine experience improved inhibitor/antagonist interest liver biopsy liver injury monocyte mortality novel novel strategies novel therapeutics patient population peripheral blood phosphoric diester hydrolase prevent probiotic therapy programs response response biomarker trefoil factor

项目摘要

DESCRIPTION (provided by applicant): This application is the translational component of an overall UO1 application entitled, "Novel therapies in alcoholic hepatitis - University of Louisvill." Alcoholic hepatitis (AH) has a high morbidity and mortality. In VA Cooperative Studies in which liver biopsies were performed, only 35% of patients with AH and underlying cirrhosis, and 60% of those with AH alone (no cirrhosis) were alive at the end of four years, with most deaths occurring early in the study. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies for AH are glucocorticoids and pentoxifylline. Both agents have anti-inflammatory activities and downregulate proinflammatory cytokines such as tumor necrosis factor (TNF). Unfortunately, an important subset of AH patients treated with glucocorticoids have "steroid resistance", and some patients have contraindications to steroid therapy. Studies on pentoxifylline in AH are limited, and efficacy appears highest in preventing/treating the hepatorenal syndrome. Thus, new therapies as well as a better understanding of mechanisms/biomarkers for severity of disease and response to therapy are necessary. Our research team has been a leader in defining mechanisms of alcohol-induced liver injury using in vitro and animal models of ALD, and in translating basic findings into the clinical setting. Our group is the first to describe dysregulated cytokine metabolism in AH. We have a long-standing interest in mechanisms of inflammation and liver injury. We also have extensive experience in the gut-liver axis and AH, as well as in the development of novel therapies for AH.!!Building on the above translational research strengths of our program which focus on the gut-liver axis and inflammation in ALD, we propose three highly translational Specific Aims, which all relate to and utilize samples from our proposed UO1 clinical trial. Aim 1 will evaluate novel mechanisms for alcohol-induced alterations in gut integriy leading to endotoxemia and AH. We will study the therapeutic efficacy of both live probiotics and probiotic supernatants. Aim 2 will study the role of specific PDE4 inhibition in AH using animal models and our AH clinical patient population. There are recent data in the pulmonary literature showing that specific PDE4 inhibitors are effective in steroid resistant patients which may translate to AH. Lastly, Aim 3 evaluates mechanisms for steroid resistance using both specimens from patients in our clinical trial and in vitro data. All three of our specific aims utiize specimens obtained from our U01 clinical trial, and our protocol interacts with the two other translational protocols in our U01 consortium. Our goal is not only to better understand mechanisms for AH, but also to develop new therapies (including those already available for other diseases) for AH, either immediately transforming clinical practice or providing novel therapies for our clinical trial consortium.

描述（由申请人提供）：此应用是题为“酒精性肝炎的新疗法 - 路易斯维尔大学的新疗法”的整体UO1申请的转化组成部分。酒精性肝炎（AH）具有高发病率和死亡率。在VA合作研究中，进行了肝活检，只有35％的AH和潜在的肝硬化患者，而单独的AH（无肝硬化）的60％的患者在四年结束时还活着，大多数死亡发生在研究的早期。对于酒精性肝病（ALD），没有FDA批准的疗法。 AH的最广泛使用的（标签外）药物疗法是糖皮质激素和五氧化胺。两种药物具有抗炎活性，并下调促炎细胞因子，例如肿瘤坏死因子（TNF）。不幸的是，接受糖皮质激素治疗的AH患者的重要子集具有“类固醇耐药性”，有些患者对类固醇治疗有禁忌症。关于AH中戊昔丁的研究有限，在预防/治疗肝综合征方面的功效似乎最高。因此，有必要对新疗法以及对疾病严重程度和对治疗反应的机制/生物标志物的更好理解。我们的研究团队一直是使用ALD的体外和动物模型定义酒精诱导肝损伤机制的领导者，并将基本发现转化为临床环境。我们的小组是第一个描述AH中细胞因子代谢失调的人。我们对炎症和肝损伤机制具有长期的兴趣。 We also have extensive experience in the gut-liver axis and AH, as well as in the development of novel therapies for AH.!!Building on the above translational research strengths of our program which focus on the gut-liver axis and inflammation in ALD, we propose three highly translational Specific Aims, which all relate to and utilize samples from our proposed UO1 clinical trial. AIM 1将评估饮酒诱导的肠道整合改变的新机制，导致内毒素血症和AH。我们将研究活益生菌和益生菌上清液的治疗功效。 AIM 2将使用动物模型和我们的AH临床患者群体研究特定PDE4在AH中的作用。肺部文献中有最新数据表明，特定的PDE4抑制剂对可能转化为AH的类固醇耐药性患者有效。最后，AIM 3使用来自临床试验和体外数据的患者的两个标本来评估类固醇耐药性的机制。我们的所有三个特定目标都从U01临床试验中获得的UTIIZE标本，我们的协议与U01财团中的其他两个翻译方案相互作用。我们的目标不仅是为了更好地了解AH的机制，而且是为AH开发新的疗法（包括已经可用于其他疾病的疗法），要么立即改变临床实践，要么为我们的临床试验财团提供新的疗法。