# Elucidating the role of Fra1 in pancreatic Kras-driven acinar to ductal metaplasia

> **NIH NIH F30** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $47,256

## Abstract

PROJECT SUMMARY (ABSTRACT)
Acute and chronic pancreatitis afflict millions of individuals in the US. Mouse models have revealed that acinar
cells can de-differentiate after pancreatic injury to a progenitor-like cell type with ductal characteristics in a
process termed acinar-to-ductal metaplasia (ADM). In the absence of oncogenic mutations, ADM lesions can
resolve and reform the acinar compartment. However, in the presence of oncogenic Kras mutations, the ADM
lesions can continue to de-differentiate to a pre-invasive pancreatic intraepithelial neoplasia (PanIN). The
mechanisms that drive PanIN formation in the context of injury and oncogenic mutations are poorly understood,
resulting in an absence of targets to combat the persistent ADM.
We have identified previously through bulk ATAC-sequencing that the transcription factor Fra1 is differentially
active only in the context of mutant Kras and acute inflammation. We have also generated a unique mouse
model expressing inducible mutant KRAS (iKras) and Fra1 loxp alleles (Fra1 KO) in a pancreatic epithelial-
specific manner. Our preliminary studies demonstrate that Fra1 loss attenuates ADM formation and
stromagenesis compared to the FRA1 WT controls. The overarching goal of this proposal is to understand how
FRA1 and its interacting partners, which constitute the AP-1 complex, govern ADM progression in the context of
mutant Kras and inflammation. My hypothesis is that FRA1 is a central mediator of ADM. I will investigate
the cell autonomous and non-cell autonomous effects driving FRA1 activation through the following
interrelated Specific Aims: (1) Investigate how Fra1 remodels chromatin in ADM after induction of
pancreatitis; (2) Elucidate the role of fibroblast-secreted G-CSF in Fra1 induction during pancreatitis. I
will use novel mouse models, ex vivo 3D acinar and ADM cell cultures, and state-of-the-art single-cell sequencing
and chromatin precipitation assays to conduct this study. This proposal also encompasses a translational aspect
by proposing G-CSFR as a novel therapeutic target for the treatment of acute pancreatitis. Additionally, this
project incorporates aspects of pathophysiology, molecular/cellular biology, and quantitative data analysis. This
proposal provides me with a robust foundation in both experimental and quantitative analysis and broadens my
fundamental knowledge of pancreatic epithelial cell homeostasis and plasticity.
With the guidance from experienced mentors (Drs. Rustgi and Sims), my advisory committee and the rich array
of resources at Columbia University Irving Medical Center, I will be able to complete my predoctoral PhD training.
Completion of this critical milestone will set the stage for my long-term goal as a physician-scientist who conducts
basic and translational research in an academic medical center with a focus on tissue inflammation, cellular
identity and plasticity, and tissue regeneration.

## Key facts

- **NIH application ID:** 10537870
- **Project number:** 1F30DK134109-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Alina Lin Li
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $47,256
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537870

## Citation

> US National Institutes of Health, RePORTER application 10537870, Elucidating the role of Fra1 in pancreatic Kras-driven acinar to ductal metaplasia (1F30DK134109-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10537870. Licensed CC0.

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