# Liver-enriched Transcription Factors as Prognostic Markers and Therapeutic Targets in Alcoholic Hepatitis

> **NIH NIH U01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $243,345

## Abstract

Bataller – UO1 (RFA AA-18-003)
ABSTRACT
Hepatocellular failure is a hallmark finding in patients with alcoholic hepatitis (AH). Current therapy
is not fully effective and targeted therapies are needed. Most research has been focused on the
role of inflammation. In contrast, the mechanisms underlying hepatocellular failure and the
subsequent poor regenerative response in AH are unknown. Our group showed that severe AH
is characterized by a massive, yet inefficient accumulation of ductular cells. The central aim of
this proposal is to identify the molecular mechanisms underlying the hepatocellular failure and the
subsequent poor regenerative response in AH. The ultimate goal is the identification of prognostic
markers and therapeutic targets useful for precision medicine. We have generated strong
preliminary data in human livers showing: (1) progression of early forms of ALD to AH is
characterized by a profound decrease in the function of HNF4A. (2) HNF4A network footprint
closely correlates with disease severity in AH patients. (3) TGFβ1 and EGF are key upstream
modulators in AH and regulate LETF in cultured human hepatocytes. (4) The gene signature of
the ductular reaction in AH shows enriched inflammatory, fibrogenic and proliferative signals and
decreased HNF4A activity. And (5) Secreted proteins encoded by LEFT-target genes are
detected in sera of patients with AH. Based on these strong preliminary data, our specific aims
are (1) To uncover the molecular mechanism of HNF4A isoform regulation by TGFβ1, by
characterizing the interactome of the HNF4A P1 dependent isoforms by MS coupled
Immunoprecipitation. Moreover, we aim at identifying the DNA binding regions of HNF4A P2
isoform by ChIPseq, and generating a promoter reporter system that will be used for in vitro high-
troughput screening of novel drugs. (2) To investigate the relevance and genomic profile of
ductular proliferation and de-differentiated hepatocytes in AH by means of RNAseq of
microdissected areas and correlation of gene signatures with clinical outcome. We have
developed human organoids of ductular reaction that represents a novel tool to study the effect
of TGFβ1 and EGFR ligands in HNF4A. And (3). To identify new serum protein biomarkers of
AH by investigating serum N-linked glycoprotein compartment by glycoprotein selection coupled
to MS and by analyzing post-translational modifications of the serum proteome by Snap-shot
proteomic array. We will combine analysis of serum proteomic data with transcriptomic studies of
total and microdissected liver tissue and correlate the resulting signatures with clinical outcomes
including mortality and response to prednisolone and G-CSF.

## Key facts

- **NIH application ID:** 10198652
- **Project number:** 5U01AA026972-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ramon Bataller
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $243,345
- **Award type:** 5
- **Project period:** 2018-09-22 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198652

## Citation

> US National Institutes of Health, RePORTER application 10198652, Liver-enriched Transcription Factors as Prognostic Markers and Therapeutic Targets in Alcoholic Hepatitis (5U01AA026972-04). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10198652. Licensed CC0.

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