Document text
Principal Investigator: ROBERT J FONTANA
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $374,400
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Accuracy of Diagnosis><Active Follow-up><Acute><Age><Algorithms><Alleles><Allelomorphs><Amox-clav><Amoxi-Clavulanate><Amoxicillin-Clavulanate Potassium><Amoxicillin-Clavulanic Acid><Amoxicillin-Potassium Clavulanate Combination><Amoxycillin-Clavulanic Acid><Analytic Chemistry><Analytical Chemistry><Ancillary Study><Applications Grants><Assay><Augmentin><Bioassay><Biological><Biological Assay><Biological Markers><Biomedical Engineering><Black><Black race><Blood Sample><Blood Serum><Blood specimen><Body Tissues><Budesonide><COVID-19><CV-19><Causality><Cell Body><Cells><Chemical Fractionation><Childhood><Clavulanate Potentiated Amoxycillin><Clinical><Clinical Data><Clinical Research><Clinical Study><Clinical Trials><Co-amoxiclav><Coamoxiclav><Collaborations><Collection><Coronavirus Infectious Disease 2019><DNA><Data><Deoxyribonucleic Acid><Development><Diagnostic><Dose><Drug Screening><Drugs><E-Mail><Early Diagnosis><Education><Education and Outreach><Educational aspects><Electronic Mail><Electronics><Email><Endothelial Cells><Enrollment><Ethnic Origin><Ethnicity><Etiology><Event><Exclusion Criteria><FRACN><Feasibility Studies><Fractionation><Fractionation Radiotherapy><Funding><GWA study><GWAS><Gender><Generations><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Genomics><Genotype><Goals><Grant><Grant Proposals><HCV><Hepatic Cells><Hepatic Parenchymal Cell><Hepatitis><Hepatitis C virus><Hepatocyte><Hepatotoxic effect><Hepatotoxicity><High Throughput Assay><Hispanic><Human><Icterus><Immunologic Factors><Immunologic Subtyping><Immunological Factors><Immunophenotyping><In Vitro><Individual><Inflammatory><Inherited Predisposition><Inherited Susceptibility><Injury to Liver><Instruction and Outreach><International><Intervention Studies><Investigators><Jaundice><LYP gene><LYP protein><Laboratories><Liver><Liver Cells><Liver Toxicity><Logistics><Lymphoid Phosphatase><Medical center><Medication><Medicine><Michigan><Modeling><Modern Man><Molecular><Monitor><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><Natural History><Natural Products><Non-Receptor Type 22 Protein Tyrosine Phosphatase><Non-Receptor Type 8 Protein Tyrosine Phosphatase><Oral><Organoids><Outcome><PBMC><PEP gene><PEP protein><PTPN22><PTPN22 gene><PTPN8><Pathogenesis><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peripheral Blood Mononuclear Cell><Pest-Domain Phosphatase><Pharmaceutical Preparations><Phenotype><Physicians><Physiologic><Physiological><Predisposition><Professional Organizations><Prospective Studies><Protocol><Protocols documentation><Publications><RNA vaccine><RNA-based vaccine><Race><Races><Registries><Reporting><Research><Research Personnel><Researchers><Retrospective Studies><Risk Factors><Safety><Sampling><Scientific Publication><Secure><Series><Serum><Site><Spain><Standardization><Steroid Compound><Steroids><Stress><Susceptibility><System><Testing><Tissues><Toxic effect on liver cells><Training and Outreach><Tutoring and Outreach><Twitter><United States><Universities><Update><Work><active followup><ages><bio-engineered><bio-engineers><bio-markers><biobank><bioengineering><biologic><biologic marker><biological engineering><biomarker><biorepository><causation><cell type><clinical trial protocol><cohort><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cost><design><designing><determine efficacy><developmental><diagnostic accuracy><disease causation><drug/agent><early detection><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><elastic imaging><elasticity imaging><elastography><electronic><electronic communication><electronic device><enroll><ethnic minority><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><follow up><follow-up><followed up><followup><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><hepatic body system><hepatic damage><hepatic injury><hepatic organ system><hepatic toxicity><hepatoxicity><high throughput screening><iPS><iPSC><iPSCs><immunologic substance><immunological substance><immunophenotype><improved><individual patient><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><injury recovery><insight><instrument><intervention research><interventional research><interventional study><interventions research><liver damage><liver injury><mRNA vaccine><mRNA-based vaccine><member><metabolism measurement><metabolomics><metabonomics><minority patient><naturally occurring product><novel><open label><open label study><operation><operations><participant enrollment><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient enrollment><patient oriented outcomes><patient-derived pluripotent stem cells><patients from minority><patients of minority><pediatric><pharmacovigilance><polygenic risk score><professional association><professional membership><professional society><prognostic><racial><racial background><racial origin><recovery after injury><recovery following injury><recovery post injury><recruit><response><tool><transcriptomics><web site><website><whole genome association analysis><whole genome association studies><whole genome association study>