Research Network for Drug-Induced Liver Disease

药物性肝病研究网络

• 批准号: 7287797
• 负责人: Petr Protiva
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287797
• 关键词: Adipose tissue; Adult; Adverse effects; Affect; Alcoholic Hepatitis; Allergic; Alternative Medicine; Bile fluid; Biliary; Biochemical; Biological; Blood; Blood specimen; Candidate Disease Gene; Case-Control Studies; Chemicals; Class; Clinical; Clinical Research; Clinical Trials; Complementary Medicine; Condition; Connecticut; Cryptogenic cirrhosis; DNA; Data; Databases; Detection; Development; Disease; Drug or Chemical; Drug usage; Early Diagnosis; Epidemiology; Exclusion; Feces; Folk Remedy; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; HIV; Health; Hepatic; Hepatitis; Hepatocyte; Hepatotoxicity; Herbal Medicine; Highly Active Antiretroviral Therapy; Human; Human Genome; Hypersensitivity; Immune; Individual; Injury; Laboratories; Liver; Liver diseases; Marketing; Metabolic Diseases; Metabolism; Methotrexate; Molecular; Network-based; Normal Range; Numbers; Organ; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacologic Substance; Physicians; Plasma; Precipitation; Principal Investigator; Prospective Studies; Proteins; Proteomics; Psoriasis; Rate; Reporting; Reproduction; Research; Research Infrastructure; Role playing therapy; Serological; Serum; Signal Transduction; Site; Steatohepatitis; Study of serum; System; Techniques; Testing; Time; Tissue Banks; Tissues; Toxic effect; Toxin; Tuberculosis; Universities; Urine; Viral hepatitis; Water; Work; alpha 1-Antitrypsin Deficiency; base; case control; drug development; drug induced liver disease; epidemiology study; instrument; interest; liver metabolism; member; non-alcoholic; novel therapeutics; programs; protein expression; repository; vector

DESCRIPTION (provided by applicant): Drugs and other chemicals have numerous salutary effects on humans, but they may also cause toxicity. Because of the central role played by the liver in metabolism, the liver is the most frequent and important site of drug- or chemical-induced tissue injury. As more drugs have been developed and used and more so-called complementary medicines (CAM) and herbal remedies are used, drug-induced liver disease (DILD) has become a problem of major and growing importance, and there is a growing need for better systems for early detection, characterization, and reporting of instances of DILD. Such systems should be applied both to drugs still under development and to drugs, CAM, and herbal remedies already on the market. The long-term aim of this research program is to develop a regional consortium and network in the Northeastern U.S.A. for the detection and clinico-pathological and molecular (genomic, proteomic) characterization of DILD. A key aspect of this work will be to develop a clinical, laboratory, and histopathological data base of "phenotypic" information on subjects with known or suspected DILD, and also to establish DNA, RNA, serum, and tissue banks on these same subjects. This will facilitate the development of "genotypic" (DNA), gene expression (RNA), and protein expression (proteomic) profiling of the same subjects, eventually permitting the detailed phenotypic-genotypic-proteomic correlations that will be possible as candidate genes and gene products involved in DILD are identified and characterized. Indeed, the regional and national data bases that will be established as a result of this program will aid us in discovering and identifying such genes and gene products, thereby bringing to fruition the enormous potential implicit in the successful sequencing of the human genome. The specific aims of this proposal are to: (1.) establish one of the national interactive Clinical Centers of the Hepatotoxicity Clinical Research Network, based at the University of Connecticut Health Center (UCHC). Our Center will serve as the coordinating center for a consortium of academic and practicing hepatologists and groups in the Northeastern U.S.A. We will take advantage of the strong research infrastructure of the UCHC Office of Clinical Research and the NIH-supported GCRC at UCHC; (2.) work with other members of the Network nationwide to develop consistent, standardized approaches and instruments to identify and fully characterize bona fide cases of drug-, CAM-, and toxin-induced liver injury, identified retrospectively. We will also obtain data from suitable control subjects thereby allowing for case-control studies, which will facilitate studies of the epidemiology and clinical spectrum of such hepatotoxicity; (3.) do prospective studies of selected, commonly used hepatotoxic drugs (HAART for HIV, INH for tuberculosis, methotrexate (MTX) for psoriasis); and (4.) obtain biological samples (blood, liver, plasma, serum) for study of the pathogenesis of DILD, using biochemical, serological, genetic, and proteomic techniques. The clinico-pathological database and the tissue and DNA repositories will permit us to create and test numerous hypotheses relating to the pathogenesis and pharmacogenomics of DILD.

描述(由申请人提供)： 药物和其他化学物质对人类有许多有益的影响，但它们也可能造成毒性。由于肝脏在新陈代谢中的中心作用，肝脏是药物或化学物质引起的组织损伤最常见和最重要的部位。随着越来越多的药物被开发和使用，越来越多的所谓补充药物(CAM)和草药被使用，药物性肝病(DILD)已经成为一个日益重要的重大问题，越来越需要更好的系统来早期发现、表征和报告DILD实例。这样的系统既应该应用于仍在开发中的药物，也应该应用于市场上已经上市的药物、CAM和草药。这项研究计划的长期目标是在美国东北部建立一个地区性协会和网络，用于DILD的检测和临床病理和分子(基因组、蛋白质组)表征。这项工作的一个关键方面将是建立一个关于已知或疑似DILD受试者的临床、实验室和组织病理学信息的数据库，并建立这些受试者的DNA、RNA、血清和组织库。这将促进相同受试者的“基因类型”(DNA)、基因表达(RNA)和蛋白质表达(蛋白质组)图谱的发展，最终允许在识别和表征参与DILD的候选基因和基因产品时可能出现的详细的表型-基因-蛋白质组相关性。事实上，作为这一计划的结果将建立的地区和国家数据库将帮助我们发现和识别此类基因和基因产品，从而实现人类基因组成功测序所隐含的巨大潜力。 这项建议的具体目的是：(1)建立设在康涅狄格大学健康中心(UCHC)的肝毒性临床研究网络国家互动临床中心之一。我们的中心将作为美国东北部学术和实践肝病专家和团体联盟的协调中心。我们将利用UCHC临床研究办公室和UCHC由NIH支持的GCRC的强大研究基础设施；(2)与该网络全国范围内的其他成员合作，制定一致、标准化的方法和工具，以确定和充分描述追溯确定的药物、CAM和毒素所致肝损伤的真实病例。我们还将从合适的对照对象那里获得数据，从而进行病例对照研究，这将有助于研究这种肝脏毒性的流行病学和临床谱系；对选定的常用肝毒性药物(HAART治疗HIV，INH治疗结核病，MTX治疗牛皮癣)进行前瞻性研究；以及(4)利用生化、血清学、遗传学和蛋白质组学技术，获取用于研究DILD发病机制的生物样本(血液、肝脏、血浆、血清)。临床病理数据库以及组织和DNA储存库将允许我们创建和测试与DILD的发病机制和药物基因组学有关的许多假说。