# TNF Alpha and Recovery from Alcoholic Liver Injury

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $494,288

## Abstract

Morbidity and mortality in alcohol-related liver diseases (ALD) are caused by severe alcohol-induced
steatohepatitis (SAH), cirrhosis, and liver cancer. Effective therapies are lacking because the mechanisms
driving the pathogenesis and progression of these conditions are unclear. This research program has evaluated
the general hypothesis that bad outcomes of alcohol-induced liver injury result from deregulated repair
mechanisms that cause defective regeneration of mature hepatocytes. Our prior results indicate that effective
liver regeneration requires reactivating fetal programs to nurture the outgrowth of liver progenitors, but then
silencing these programs so that the liver matures. Thus, we will next evaluate the hypothesis that alcohol-related
liver diseases progress because mechanisms controlling when fetal programs are switched on and off in adult
liver cells are dysregulated. We have evidence that liver failure in human SAH results from over-activation of
fetal programs. Conversely, our pre-clinical data suggest that cirrhosis evolves when adult programs are not
suppressed sufficiently for injured livers to regenerate. To define tractable mechanisms that control adult-fetal
“switching” in hepatocytes of alcohol-injured livers we will leverage our recently published data which show that
the RNA binding protein ESRP2 is critically important for switching on the adult program in developing livers,
and that over-expressing ESRP2 blocks adult liver regeneration. ESRP2 regulates the splicing of ~20% of
hepatocyte RNAs, generating splice variants that encode functional differences in proteins that control
hepatocyte proliferation and differentiation. Aims 1 and 2 will use ESRP2-knockout and over-expressing mice to
determine how manipulating fetal RNA splicing programs impacts progression of alcohol-induced liver injury. In
Aim 3 next generation sequencing and computational analysis will identify a conserved repertoire of RNA binding
proteins, RNA splice variants, and liver genes that change in response to alcohol-induced liver injury in both
mice and humans, thereby revealing novel therapeutic targets to improve recovery from ALD.

## Key facts

- **NIH application ID:** 10459397
- **Project number:** 5R01AA010154-27
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** ANNA MAE ELIZABETH DIEHL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $494,288
- **Award type:** 5
- **Project period:** 1994-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459397

## Citation

> US National Institutes of Health, RePORTER application 10459397, TNF Alpha and Recovery from Alcoholic Liver Injury (5R01AA010154-27). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459397. Licensed CC0.

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