Michigan Hepatotoxicity Clinical Research Network Renewal

点击翻译按钮获取中文摘要

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.