# Role of m6A modification in Alpha 1-antitrypsin deficiency induces liver disease

> **NIH NIH R21** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $104,482

## Abstract

PROJECT SUMMARY
Alpha1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in
children and the most frequent inherited indication for liver failure and transplantation in the
pediatric population. However, the clinical course of AATD-related liver disease is highly
variable. The majority of infants with homozygous severe AATD (PiZZ) clinically recover in early
childhood through the unknown adaptive mechanisms. Epidemiological studies give rise to three
outstanding questions in the field. They are: (1) What are the mechanisms of adaptation to the
misfolded AAT accumulation in the lumen of ER? (2) Do the mechanisms of adaptation only
response to misfolded AAT or also target other unfolded proteins? and (3) Can we design
therapeutic strategies to directly use these mechanisms of adaptation? Here, we identified a
novel alpha1-antitrypsin deficiency adaptive mechanism, ER proteotoxic stress-m6A pathway or
ERm6A : Unfolded Alpha1-antitrypsin protein accumulation induces N6-adenosine-
methyltransferase 14 (METTL14) elevation to increase m6A mRNA methylation of C/EBP
Homologous Protein (CHOP), which suppresses CHOP translation and reduces expression of
its downstream pro-apoptotic target genes, apoptosis and liver injury. We propose that ERm6A
regulates ER proteotoxic stress at the epitranscriptional level, through a mechanism that is
distinct from any other previously described ER proteotoxic stress-associated signaling
pathway, including the well-known canonical (transcriptional and translational level) UPR
pathway. We will test the central hypothesis that METTL14, induced by unfolded protein
accumulation, suppresses cell death and liver hepatotoxicity (Aim 1.1) by modulating CHOP 5′
UTR m6A modification (Aim 1.2). This proposal addresses the mission of the NICHD by
rigorously investigating the molecular mechanisms of AATD-induced liver injury with the
potential to improve health for large numbers of children.

## Key facts

- **NIH application ID:** 11024872
- **Project number:** 7R21HD104904-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Juncheng Wei
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $104,482
- **Award type:** 7
- **Project period:** 2023-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11024872

## Citation

> US National Institutes of Health, RePORTER application 11024872, Role of m6A modification in Alpha 1-antitrypsin deficiency induces liver disease (7R21HD104904-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11024872. Licensed CC0.

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