# Michigan Hepatotoxicity Clinical Research Network Renewal

> **NIH NIH U01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $374,400

## Abstract

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...

## Key facts

- **NIH application ID:** 10918328
- **Project number:** 5U01DK065184-22
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ROBERT J FONTANA
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $374,400
- **Award type:** 5
- **Project period:** 2003-09-30 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918328

## Citation

> US National Institutes of Health, RePORTER application 10918328, Michigan Hepatotoxicity Clinical Research Network Renewal (5U01DK065184-22). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10918328. Licensed CC0.

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