Michigan Hepatotoxicity Clinical Research Network Renewal

密歇根肝毒性临床研究网络更新

• 批准号: 10730426
• 负责人: ROBERT J FONTANA
• 金额: $ 37.74万
• 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 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730426
• 关键词: Acute; Age; Algorithms; Alleles; Amoxicillin-Potassium Clavulanate Combination; Analytical Chemistry; Ancillary Study; Applications Grants; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Black race; Blood specimen; Budesonide; COVID-19; Cells; Childhood; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Collection; DNA; Data; Development; Diagnostic; Dose; Drug Screening; Early Diagnosis; Education; Education and Outreach; Electronic Mail; Electronics; Endothelial Cells; Enrollment; Ethnic Origin; Etiology; Event; Exclusion Criteria; Feasibility Studies; Fractionation; Funding; Gender; Generations; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Grant; Hepatitis; Hepatitis C virus; Hepatocyte; Hepatotoxicity; Hispanic; Human; Icterus; Immunologic Factors; Immunophenotyping; In Vitro; Individual; Inflammatory; International; Intervention Studies; Laboratories; Liver; Logistics; Medical center; Medicine; Michigan; Modeling; Molecular; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; Natural Products; Oral; Organoids; Outcome; PTPN22 gene; Pathogenesis; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Physicians; Physiological; Predisposition; Professional Organizations; Prospective Studies; Protocols documentation; Publications; RNA vaccine; Race; Registries; Reporting; Research; Research Personnel; Retrospective Studies; Risk Factors; Safety; Sampling; Secure; Series; Serum; Site; Spain; Standardization; Steroids; Stress; System; Testing; Tissues; Twitter; United States; Universities; Update; Work; biobank; cell type; clinical trial protocol; cohort; cost; design; diagnostic accuracy; efficacy evaluation; elastography; ethnic minority; experimental study; follow-up; genome wide association study; high throughput screening; improved; individual patient; induced pluripotent stem cell; injury recovery; insight; instrument; liver injury; member; metabolomics; minority patient; novel; open label; operation; participant enrollment; pharmacovigilance; polygenic risk score; prognostic; recruit; response; tool; transcriptomics; web site

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.

摘要

项目成果

Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network.

• DOI: 10.1002/hep.27157
• 发表时间: 2014-08
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Russo, Mark W.;Hoofnagle, Jay H.;Gu, Jiezhun;Fontana, Robert J.;Barnhart, Huiman;Kleiner, David E.;Chalasani, Naga;Bonkovsky, Herbert L.
• 通讯作者: Bonkovsky, Herbert L.

Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct.

• DOI: 10.2165/00002018-200932010-00005
• 发表时间: 2009
• 期刊: Drug safety
• 影响因子: 4.2
• 作者: Fontana RJ;Watkins PB;Bonkovsky HL;Chalasani N;Davern T;Serrano J;Rochon J;DILIN Study Group
• 通讯作者: DILIN Study Group

Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

干细胞衍生的模型，以提高对人类药物诱导的肝损伤的机械理解和预测。

• DOI: 10.1002/hep.28886
• 发表时间: 2017-02
• 期刊: Hepatology (Baltimore, Md.)
• 作者: Goldring C;Antoine DJ;Bonner F;Crozier J;Denning C;Fontana RJ;Hanley NA;Hay DC;Ingelman-Sundberg M;Juhila S;Kitteringham N;Silva-Lima B;Norris A;Pridgeon C;Ross JA;Young RS;Tagle D;Tornesi B;van de Water B;Weaver RJ;Zhang F;Park BK
• 通讯作者: Park BK

Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study.

• DOI: 10.1097/mpg.0b013e31821d6cfd
• 发表时间: 2011-08
• 期刊: Journal of pediatric gastroenterology and nutrition
• 影响因子: 2.9
• 作者: Molleston JP;Fontana RJ;Lopez MJ;Kleiner DE;Gu J;Chalasani N;Drug-Induced Liver Injury Network
• 通讯作者: Drug-Induced Liver Injury Network

Serum proteomic profiling in patients with drug-induced liver injury.

• DOI: 10.1111/j.1365-2036.2011.04982.x
• 发表时间: 2012-03
• 期刊: Alimentary pharmacology & therapeutics
• 影响因子: 7.6
• 作者: Bell LN;Vuppalanchi R;Watkins PB;Bonkovsky HL;Serrano J;Fontana RJ;Wang M;Rochon J;Chalasani N;US Drug-Induced Liver Injury Network (DILIN) Research Group
• 通讯作者: US Drug-Induced Liver Injury Network (DILIN) Research Group