Michigan Hepatotoxicity Clinical Research Network

密歇根肝毒性临床研究网络

• 批准号: 7591287
• 负责人: ROBERT J FONTANA
• 金额: $ 27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591287
• 关键词: Acute Liver Failure; Adult; Amoxicillin; Awareness; Bioinformatics; Biological; Biological Markers; Candidate Disease Gene; Childhood; Class; Clavulanate; Clinical; Clinical Data; Clinical Research; Communities; DNA; Data; Databases; Development; Diagnosis; Educational Activities; Enrollment; Etiology; Excision; Family member; Follow-Up Studies; Future; Gene Targeting; General Population; Genetic; Genome; Genotype; Geographic Distribution; Hepatotoxicity; Immunologics; Injury; Knowledge; Lead; Literature; Liver; Medical; Michigan; National Institute of Diabetes and Digestive and Kidney Diseases; Numbers; Outcome; Outcome Study; Patient Recruitments; Patients; Performance; Pharmaceutical Preparations; Pharmacogenetics; Pharmacologic Substance; Phenotype; Phenytoin; Physicians; Plasma; Predisposition; Prevention; Prospective Studies; Reaction; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Retrospective Studies; Risk Factors; Sampling; Scientist; Severities; Severity of illness; Single Nucleotide Polymorphism; Site; Testing; Therapeutic; Tissue Sample; United States; United States National Library of Medicine; Universities; Urine; Validation; base; case control; clinical research site; data acquisition; follow-up; genetic profiling; genetic risk factor; improved; insight; instrument; isoniazid; novel; novel diagnostics; outreach; prognostic; valproate

DESCRIPTION (provided by applicant): Drug induced liver injury (DILI) is an uncommon adverse drug reaction (ADR) of increasing importance to the medical community, pharmaceutical, regulatory agencies, and the general public. DILI is the leading cause of acute liver failure in the United States and the leading reason for discontinuation of drugs in development as well as removal of approved drugs from the marketplace. The Drug Induced Liver Injury Network (DILIN) was established in 2003 to advance understanding and research into DILI. The Retrospective study has collected DNA samples from 58 subjects with liver injury attributed to amoxicillin/clavulanate, valproate, phenytoin, isoniazid for future pharmacogenetic and mechanistic studies. In addition, over 400 patients with DILI due to a multitude of medications and herbal products have been enrolled into the Prospective study wherein DNA, serum, plasma, urine, and liver tissue samples as well as extensive clinical data are collected. To build upon the growing repository of data, biological samples, and research expertise, a competing renewal with expansion of the number of DILIN clinical sites is proposed. The primary aim of this proposal is to continue to enroll bonafide DILI patients with varying disease severity recruited from the Michigan Hepatoxicity Research Network into the DILIN Prospective study at the University of Michigan. A causality assessment instrument as well as novel diagnostic and prognostic biomarkers will be developed from the collected clinical data and biological samples. The secondary aim of this proposal is to conduct pharmacogenetic analyses of DNA samples collected from the DILI cases and controls. Whole genome SNP analyses and/or targeted gene approaches are proposed to help elucidate the contribution of host pharmacogenetics in the susceptibility and outcome of DILI. A Genetic Profiling Committee with bioinformatics expertise is proposed to analyze and interpret the pharmacogenetic data and help formulate additional hypothesis driven mechanistic studies. Finally, maintaining contact with the DILI case patients for up to 20 years after enrollment will allow performance of confirmatory genotype-phenotype association and other follow-up studies in DILI patients, family members, and controls. These supplemental studies may lead to the identification and refinement of genetic biomarkers to assist in the prevention, diagnosis and management of future DILI patients. The third aim of this proposal is to develop an authoritative and comprehensive LiverTox website in conjunction with the National Library of Medicine to help educate and assist practicing physicians, researchers, and the general public on DILI. A LiverTox website will not only improve worldwide knowledge and awareness of DILI but also potentially enhance recruitment for the DILIN Prospective study and other future initiatives.

描述（由申请人提供）： 药物性肝损伤 (DILI) 是一种罕见的药物不良反应 (ADR)，对医学界、制药、监管机构和公众越来越重要。药源性肝损伤是美国急性肝衰竭的主要原因，也是停止开发药物以及从市场上撤下已批准药物的主要原因。药物性肝损伤网络 (DILIN) 成立于 2003 年，旨在促进对 DILI 的了解和研究。这项回顾性研究收集了 58 名因阿莫西林/克拉维酸、丙戊酸、苯妥英、异烟肼导致肝损伤的受试者的 DNA 样本，用于未来的药物遗传学和机制研究。此外，超过 400 名因多种药物和草药产品而导致 DILI 的患者已被纳入前瞻性研究，其中收集了 DNA、血清、血浆、尿液和肝组织样本以及广泛的临床数据。为了建立在不断增长的数据、生物样本和研究专业知识库的基础上，提出了与 DILIN 临床站点数量扩张相竞争的更新。该提案的主要目的是继续将从密歇根肝毒性研究网络招募的患有不同疾病严重程度的真正 DILI 患者纳入密歇根大学的 DILIN 前瞻性研究。将根据收集的临床数据和生物样本开发因果关系评估工具以及新型诊断和预后生物标志物。该提案的第二个目标是对从 DILI 病例和对照中收集的 DNA 样本进行药物遗传学分析。提出全基因组 SNP 分析和/或靶向基因方法来帮助阐明宿主药物遗传学在 DILI 的易感性和结果中的贡献。建议成立具有生物信息学专业知识的遗传分析委员会来分析和解释药物遗传学数据，并帮助制定其他假设驱动的机制研究。最后，在入组后与 DILI 病例患者保持长达 20 年的联系将允许在 DILI 患者、家庭成员和对照中进行确认性基因型-表型关联和其他后续研究。这些补充研究可能有助于识别和完善遗传生物标志物，以协助预防、诊断和管理未来的 DILI 患者。该提案的第三个目标是与国家医学图书馆合作开发一个权威且全面的 LiverTox 网站，以帮助教育和协助执业医生、研究人员和公众进行 DILI。 LiverTox 网站不仅将提高全球对 DILI 的了解和认识，而且有可能加强 DILIN 前瞻性研究和其他未来计划的招募。