Research Network for Drug-Induced Liver Disease

药物性肝病研究网络

基本信息

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
项目类别：
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

项目摘要

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，但也可能引起毒性。由于肝脏在代谢中起着核心作用，因此肝脏是药物或化学诱导的组织损伤的最常见，最重要的部位。随着越来越多的药物的开发和使用，使用了更多所谓的互补药物（CAM）和草药疗法，药物诱导的肝病（DILD）已成为重大和重要性的一个问题，并且越来越需要对早期检测，表征和DILD实例报告的更好系统的需求。这种系统应既应应用于仍在开发中的药物，以及已经在市场上的药物，CAM和草药。该研究计划的长期目的是在美国东北部开发一个区域财团和网络。用于检测和临床病理学和分子（基因组，蛋白质组学）的DILD。这项工作的一个关键方面是，在具有已知或怀疑的DILD受试者的“表型”信息中开发临床，实验室和组织病理学数据库，并在这些相同的受试者上建立DNA，RNA，血清和组织库。这将促进同一受试者的“基因型”（DNA），基因表达（RNA）和蛋白质表达（蛋白质组学）分析，最终允许将涉及降低的降低基因和基因产物的详细表型基因型蛋白质相关性标识和表征。实际上，由于该计划而建立的区域和国家数据基础将有助于我们发现和识别此类基因和基因产品，从而实现了人类基因组成功测序中隐含的巨大潜力。该提案的具体目的是：（1。）建立位于康涅狄格大学健康中心（UCHC）的肝毒性临床研究网络的国家互动临床中心之一。我们的中心将作为美国东北部的学术和实践肝科医生和团体的协调中心。我们将利用UCHC临床研究办公室的强大研究基础设施以及NIH支持的GCRC AT uCHC；（2.）与全国其他网络成员合作，开发一致的，标准化的方法和工具，以识别和充分表征药物，CAM和毒素引起的肝损伤的真正病例。我们还将从合适的对照对象中获取数据，从而允许病例对照研究，这将促进对这种肝毒性的流行病学和临床谱的研究；（3.）对常用的，常用的肝毒性药物（HAART HIV，INH用于结核病，甲氨蝶呤（MTX）用于牛皮癣）进行前瞻性研究；（4.）使用生化，血清学，遗传学和蛋白质组学技术获得生物学样品（血液，肝脏，血清，血清，血清，血清），以研究DILD的发病机理。临床病理数据库以及组织和DNA存储库将使我们能够创建和检验与DILD的发病机理和药物基因组学有关的许多假设。