Research Network for Drug-Induced Liver Disease

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，但它们也可能导致毒性。由于肝脏在代谢中发挥的核心作用，肝脏是药物或化学品诱导的组织损伤的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，以及越来越多的所谓的补充药物（CAM）和草药被使用，药物性肝病（DILD）已成为一个重要且日益重要的问题，并且越来越需要更好的系统来早期检测，表征和报告DILD的情况。这种系统应适用于仍在开发中的药物和已上市的药物、CAM和草药。该研究计划的长期目标是在美国东北部建立一个区域联盟和网络，用于DILD的检测和临床病理学和分子（基因组学，蛋白质组学）表征。这项工作的一个关键方面将是开发一个临床，实验室和组织病理学数据库的“表型”信息的受试者与已知或疑似DILD，并建立DNA，RNA，血清和组织库，这些相同的主题。这将有助于开发相同受试者的“基因型”（DNA）、基因表达（RNA）和蛋白质表达（蛋白质组学）谱，最终允许详细的表型-基因型-蛋白质组学相关性，这将可能作为DILD中涉及的候选基因和基因产物被鉴定和表征。事实上，作为这一计划的结果，将建立的区域和国家数据库将帮助我们发现和鉴定这些基因和基因产物，从而实现人类基因组测序成功所蕴含的巨大潜力。 本提案的具体目标是：（1.）在康涅狄格大学健康中心（UCHC）建立肝毒性临床研究网络的国家互动临床中心之一。我们的中心将作为协调中心的学术和执业肝病学家和团体在美国东北部的联盟，我们将利用UCHC临床研究办公室和NIH支持的GCRC在UCHC强大的研究基础设施;（2）。与全国网络的其他成员合作，开发一致的标准化方法和工具，以识别和充分描述回顾性识别的药物、CAM和毒素诱导的肝损伤的真实病例。我们还将从合适的对照受试者中获得数据，从而允许进行病例对照研究，这将促进此类肝毒性的流行病学和临床谱的研究;（3）对选定的常用肝毒性药物（HAART治疗HIV，INH治疗结核病，甲氨蝶呤（MTX）治疗银屑病）进行前瞻性研究;以及（4.）使用生物化学、血清学、遗传学和蛋白质组学技术获得生物样品（血液、肝脏、血浆、血清）用于DILD发病机制的研究。临床病理学数据库和组织及DNA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相关的许多假设。

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.