Hepatotoxicity Clinical Research Network

描述（由申请人提供）： 肝毒性或药物诱导的肝损伤（DIL1）目前是美国暴发性肝衰竭的最常见原因，并且是药物市场撤回的主要适应症，因此，它是具有巨大的医学、金融、法律的和监管重要性的问题。尽管大量的药物、毒素和替代药物具有引起肝毒性的潜力，但是严重的DIL1是一个足够罕见的问题，需要大量的专门研究人员协同工作以更好地理解DIL1的发病机制并开发有效的预防和治疗策略。该提案汇集了一个独特的、多学科的研究者和资源联盟，集中在北方加州，但也包括全国各地的研究中心，并计划在肝毒性临床研究网络（HCRN）中建立一个参与临床中心。我们的研究计划描述了，首先，建立一个大型多组分临床中心患者数据库，这将有助于拟议的多中心HCRN。所提出的DIL1患者信息数据库、血清、DNA和组织库将包括源自若干来源的前瞻性群组，每个来源提供不同的流行病学方面和研究潜力。其中包括加州大学旧金山分校、斯坦福大学和加州太平洋医疗中心的肝移植项目，旧金山弗朗西斯科总医院、波士顿大学、埃默里大学、波多黎各大学和路易斯安那州健康科学中心的结核病诊所，以及旧金山弗朗西斯科总医院的艾滋病诊所。在每个研究中心，我们都制定了策略，以前瞻性的方式识别明确的毒素诱导的肝损伤病例，这将允许仔细收集详细的流行病学和临床信息，以及血清、DNA和组织样本，用于生化、药理学和遗传学研究。我们计划基于提出的操作诊断标准初步鉴定具有潜在DILl的患者，然后使用经验证的因果关系评估工具进一步评估病例。将前瞻性地随访使用该仪器分类为具有“高度可能的”DIL1的患者，以便更好地定义DIL1的自然史。鉴定这种DIL1相关的多态性是开发合理的基于基因的预防策略的必要的第一步。我们预计，我们的临床中心将从种族和种族多样化的患者人群中招募约120例病例和匹配良好的对照，以供国家HCRN网络使用。我们有一个组织良好的，多学科的医生，科学家和研究护士小组，他们致力于该临床中心和整个国家肝毒性临床研究网络的成功。

DESCRIPTION (provided by applicant): Hepatotoxicity, or drug-induced liver inury (DILl), is currently the most common cause of fulminant hepatic failure in the United States and the main indication for market withdrawal of drugs and, thus, it is a problem of enormous medical, financial, legal and regulatory importance. Although a vast number of drugs, toxins and alternative medications have the potential to cause hepatotoxcity, severe DILl is a problem of sufficient rarity that a large group of dedicated investigators working in a coordinated effort will be required to better understand the pathogenesis of DILl and develop effective prevention and treatment strategies. This proposal brings together a unique, multi-disciplinary consortium of investigators and resources, concentrated within Northern California but also including sites across the country, with a plan for a participating Clinical Center in the Hepatotoxicity Clinical Research Network (HCRN). Our research plan describes, firstly, the establishment of a large multicomponent Clinical Center patient database that would contribute to the proposed multicenter HCRN. The proposed DILl patient informational database, serum, DNA and tissue bank will comprise a prospective cohort derived from several sources, each providing distinct epidemiological facets and research potential. These include the Liver Transplant Programs at UCSF, Stanford University and California Pacific Medical Center, the Tuberculosis Clinics at San Francisco General Hospital, Boston University, Emory University, University of Puerto Rico, and Louisiana Health Sciences Center, and the HIV Clinic at San Francisco General Hospital. At each site, we have developed strategies to identify well-defined cases of toxin-induced liver injury in a prospective manner that will permit careful collection of detailed epidemiological and clinical information, as well as serum, DNA and tissue samples for biochemical, pharmacological and genetic studies. We plan to initially identify patients with potential DILl based on proposed operational diagnostic criteria and then further evaluate cases using a validated causality assessment instrument. Patients classified as having "highly probable" DILl using this instrument will be followed prospectively in order to better define the natural history of DILl. Identification of such DILl-associated polymorphisms is an essential first step in the development of a rational gene-based prevention strategy. We anticipate that our Clinical Center will recruit approximately 120 cases and well-matched controls from an ethnically and racially diverse patient population to the national HCRN network. We have a well-organized, multi-disciplinary group of physicians, scientists, and research nurses who are dedicated to the success of this Clinical Center and the overall National Hepatoxicity Clinical Research Network.