Michigan Hepatotoxicity Clinical Research Network Renewal

摘要 在过去的5年里，DILIN前瞻性和回溯性研究导致了DILI的显著改善 因果关系评估(例如RECAM、丙型肝炎病毒/戊型肝炎病毒检测)和对风险因素和结果的更好理解 帝力因个别药品和HDS产品。机械论的见解包括将PTPN22确定为DILI 跨多种药物和患者种族的易感因素，奥格门汀DILI的多基因风险分数，以及其他 药物特异性的人类白细胞抗原等位基因关联。此外，我们密歇根大学的网站已经创造了人类肝脏有机化合物 来自DILIN患者的IPSC来源的肝细胞的(HLO)提供了一个令人兴奋和前所未有的机会 用384孔板进行高通量筛选，在个体患者水平上研究DILI的机制 作为生物工程双腔肝脏芯片系统。在接下来的5年里，我们的主要目标是招收更多的高 不同年龄、性别和种族的帝力病例的因果关系，用于进一步的遗传易感性和自然历史研究。至 为此，我们提出了新的合作调查员和招聘网站，使用了EMR搜索算法，并增加了 与其他主要医疗中心和附近的社区成员合作招收少数民族患者 密歇根州肝毒性网络。我们的第二个目标是对诊断和预后进行新的辅助研究 使用利用临床数据的基因组、转录组和代谢组发现方法的DILI生物标记物， 来自登记患者的生物样本和HDS产品。我们还建议提高我们对 通过分析4年肝脏弹性成像数据对DILI患者的长期预后进行分析，并提出改善 通过将基因数据与国际合作者结合起来，提高RECAM的诊断准确性。在……里面 此外，我们建议从密歇根州的GWA型DILIN患者中建立多达50个HLO株来探索 DILI发病机制中的细胞和分子事件及IPSC来源的肝窦内皮细胞的整合 细胞和外周血单核细胞进入HLO测试系统。我们的第三个目标是使DILIN成为国家药物警戒系统 可以可靠地检测和报告美国肝毒性的新原因。为达致这个目标，我们建议 通过电子平台与FDA、AASLD、AGA和其他专业协会的成员更定期地互动 并扩大了DILIN赞助的@livertox推特账户。我们还提议改造DILIN.org网站 为从业者提供更多有用的临床数据和工具，并更新livertox网站的药物可能性分数 并在HDS肝脏毒性方面开创新的篇章。最后，我们提出了一个由AASLD来承担操作的框架 在DILIN完成后，LiverTox网站的。我们的第四个目标是建议布地奈德在 重症急性肝细胞性地塞米松和黄疸患者。本研究的目的是确定Short-Rate的疗效。 长期开放标签口服布地奈德促进肝损伤恢复与同期未治疗队列的比较 与倾向相匹配的对照组。自2003年以来，我们作为DILIN注册表研究的领先参与者， 成功设计和执行信息丰富的辅助研究，我们相信密歇根大学有能力提供帮助 DILIN在未来5年内实现其目标。

ABSTRACT Over the past 5 years, the DILIN Prospective and Retrospective studies have led to significant improvements in DILI causality assessment (e.g. RECAM, HCV/ HEV testing) and improved understanding of the risk factors and outcomes of DILI due to individual drugs and HDS products. Mechanistic insights include the identification of PTPN22 as a DILI susceptibility factor across multiple drugs and patient ethnicities, a polygenic risk score for augmentin DILI, and other drug-specific HLA allele associations. Furthermore, our University of Michigan site has created human liver organoids (HLO) from iPSC-derived hepatocytes from DILIN patients that provide an exciting and unprecedented opportunity to study DILI mechanisms in vitro at the individual patient level using a 384 well plate for high throughput screening as well as a bioengineered dual chamber liver chip system. In the next 5 years, our PRIMARY AIM is to enroll additional high causality DILI cases of varying age, gender, and ethnicity for further genetic susceptibility and natural history studies. To accomplish this, we propose new co-investigators and recruitment sites, use of EMR searching algorithms, and increased enrollment of ethnic minority patients by collaborating with other major medical centers and nearby members of the Michigan Hepatotoxicity Network. Our SECOND AIM is to perform novel ancillary studies of diagnostic and prognostic DILI biomarkers using genomic, transcriptomic, and metabolomic discovery approaches that utilize the clinical data, biological samples and HDS products from enrolled patients. We also propose to improve our understanding of the long-term outcomes in DILI patients by analyzing the 4-year liver elastography data and propose to improve the diagnostic accuracy of the RECAM by incorporating genetic data in conjunction with international collaborators. In addition, we propose to develop up to 50 total HLO lines from GWAS genotyped DILIN patients at Michigan to explore the cellular and molecular events underlying DILI pathogenesis and incorporate iPSC-derived liver sinusoidal endothelial cells and PBMCs into the HLO test system. Our THIRD AIM is for DILIN to become a national pharmacovigilance system that can reliably detect and report new causes of hepatotoxicity in the United States. To accomplish this, we propose to interact more regularly with members of the FDA, AASLD, AGA, and other professional societies via electronic platforms and expansion of the DILIN sponsored @Livertox TWITTER account. We also propose to revamp the DILIN.org website to provide more useful clinical data and tools for practicioners and update the LiverTox website drug likelihood scores and create new chapters on HDS hepatotoxicity. Lastly, we propose a framework for the AASLD to assume the operation of the LiverTox website after DILIN is completed. Our FOURTH AIM is to propose a pilot clinical trial of budesonide in patients with severe acute hepatocelular DILI and jaundice. The aim of this study is to determine the efficacy of short- term open-label oral budesonide in hastening liver injury recovery compared to a contemporaneous cohort of untreated propensity-matched controls. With our track record as a leading enroller in the DILIN Registry studies since 2003 and the successful design and execution of informative ancillary studies, we believe that Michigan is well equipped to help DILIN achieve its goals in the next 5 years.