Novel Therapies in Alcoholic Hepatitis - UMMS Admin Core

酒精性肝炎的新疗法 - UMMS 管理核心

• 批准号: 8544967
• 负责人: Gyongyi Szabo
• 金额: $ 3.87万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544967
• 关键词: Acute; Advisory Committees; Alcohol dependence; Alcoholic Hepatitis; Alcoholic Liver Diseases; Applications Grants; Basic Science; Biological Markers; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Communication; Complement Activation; Complex; Data; Data Collection; Databases; Disease; Disease Outcome; Doctor of Medicine; Ensure; European; Evaluation; Genomics; Goals; Human; Individual; Informatics; Institution; Interleukin-1; Intestines; Lead; Leadership; Liver; Liver diseases; Massachusetts; MicroRNAs; Mission; Morbidity - disease rate; Mus; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Patients; Permeability; Physicians; Placebos; Principal Investigator; Probiotics; Progress Reports; Recruitment Activity; Research; Research Personnel; Resource Allocation; Safety; Schedule; Scientist; Serum; Staging; Steatohepatitis; Steroids; Testing; Therapeutic; Translational Research; United States; Universities; Urine; Work; Zinc; anakinra; base; bench to bedside; clinically relevant; immune activation; innovation; interest; medical schools; meetings; mortality; mouse model; novel; novel therapeutic intervention; pre-clinical; preclinical study; problem drinker; receptor; repository; response; standard of care; symposium; tool; treatment strategy; web site

DESCRIPTION (provided by applicant): This U01 grant application in response to "RFA - AA-12-007 for Translational Research in Alcoholic Hepatitis" is to test novel therapeutic approaches and reveal new biomarkers in alcoholic hepatitis. Alcoholic hepatitis carries high mortality and the current standard therapy with steroids is suboptimal. Because the pathogenesis of alcoholic hepatitis involves complex interactions between innate immune activation, impaired intestinal permeability and activation of cellular death pathways, we hypothesize that clinically effective new therapy should include combined therapeutic approaches that target all critical components of disease pathology. Based on preclinical data in mice and human safety, we propose to compare standard of care with steroids with a combination of pentoxiphylline plus IL-1 receptor antagonist (anakinra) plus zinc treatment in patients with acute severe alcoholic hepatitis. In patients with moderate alcoholic hepatitis the efficacy of probiotic therapy will be tested against placebo. This U01 application build on the collaboration of leading scientists in alcoholic liver disease with clinical, translational and basic research expertize from the University of Massachusetts, Cleveland Clinic, University of Louisville and UT Southwestern Medical Schools with the goal to test novel therapies, discover unique disease stage- and therapeutic response-specific biomarkers using dynamic bench-to-bedside and bedside-to-bench approaches. Biomarker analyses will include serum microRNAs, unique breath and urine markers to establish new predictors of disease outcome and treatment strategies. Preclinical studies in a mouse model will test candidate compounds to inhibit complement activation and strategies through FXR activation that may prove to be clinical candidates in the latter half of the project i the clinical trial component. To enhance the scientific potential and translational impact of this consortium, the lead PIs recruited participation of leading experts for the translational projects including Victor Ambros, the discoverer of microRNAs and Charis Eng, an internationally recognized expert in integrative genomic analysis for diseases. The Advisory Board will bring together Bruce Beutler, 2011 Nobel Laureate for discoveries in innate immunity, Willis Maddrey, the lead clinical expert in alcoholic hepatitis in the USA, Anna Mae Diehl, a highly distinguished leader in the field of steatohepatitis, and Christopher Day from the UK who is a physician scientist in the UK-European steatohepatitis translational research field. Participating investigators and institutions are as follows: Dr. Arthur McCullough Cleveland Clinic Dr. Laura Nagy Cleveland Clinic Dr. Craig McClain University of Louisville Dr. Mack C. Mitchell, Jr., M.D. U. T. Southwestern Medical School Dr. Gyongyi Szabo University of Massachusetts Medical School

描述(申请人提供)：本U01申请是为了响应“RFA-AA-12-007酒精性肝炎的转译研究”，测试新的治疗方法，并揭示酒精性肝炎的新生物标志物。酒精性肝炎具有很高的死亡率，目前使用类固醇的标准治疗方案并不理想。由于酒精性肝炎的发病机制涉及先天性免疫激活、肠道通透性受损和细胞死亡途径激活之间的复杂相互作用，我们假设临床有效的新疗法应该包括针对疾病病理的所有关键组成部分的综合治疗方法。基于小鼠的临床前数据和人类的安全性，我们建议对急性重型酒精性肝炎患者使用激素的标准护理进行比较，其中包括己酮可可碱+IL-1受体拮抗剂(Anakinra)+锌治疗。在中度酒精性肝炎患者中，益生菌治疗的有效性将受到 安慰剂。这个U01应用程序建立在酒精性肝病领域的领先科学家与来自马萨诸塞大学、克利夫兰诊所、路易斯维尔大学和德克萨斯大学西南医学院的临床、转化和基础研究专家的合作基础上，目的是测试新的治疗方法，使用动态的床到床和床到床的方法发现独特的疾病阶段和治疗反应特定的生物标记物。生物标记物分析将包括血清微RNA、独特的呼吸和尿液标记物，以建立新的疾病结局预测因素和治疗策略。小鼠模型的临床前研究将测试通过FXR激活抑制补体激活的候选化合物和策略，这些可能被证明是项目I临床试验部分的后半部分临床候选化合物。为了加强该联盟的科学潜力和翻译影响，牵头的私营部门招募了翻译项目的主要专家参加，其中包括microRNAs的发现者Victor Ambros和国际公认的疾病综合基因组分析专家Charis Eng。咨询委员会成员将包括因在先天性免疫方面的发现而获得2011年诺贝尔奖的Bruce Beutler、美国酒精性肝炎首席临床专家Willis Maddrey、脂肪性肝炎领域的杰出领导者Anna Mae Diehl以及英国的Christopher Day，他是英国-欧洲脂肪性肝炎转化研究领域的内科科学家。参与调查的研究人员和机构如下：Arthur McCullough博士克利夫兰诊所Laura Nagy克利夫兰诊所Craig McClain博士路易斯维尔大学Mack C.Mitchell，Jr.马萨诸塞大学西南医学院Gyongyi Szabo博士