# Defining the molecular determinants of inflammatory memory in the pancreas

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $506,546

## Abstract

Project Summary / Abstract
Biological systems operate within fluctuating environments, and, therefore, are inherently tasked with accurately
responding in real-time to a myriad of signals. Recent evidence suggests that a memory of inflammation can be
encoded and retained in the epigenome of cells even following resolution of the initial stimulus. The presence of
`inflammatory memory' suggests that preservation of tissue homeostasis also incorporates an evolutionary
adaptation in which future responses are educated by past experiences.
Inflammation is essential to the disruption of tissue homeostasis, and, in the pancreas, can destabilize the identity
of terminally differentiated acinar cells. Recently, we have employed lineage-traced mouse models to delineate
the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and
unveiled the presence of an epigenetic memory of inflammation in the pancreatic acinar cell compartment. We
have observed that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular
baseline after several months, representing an incomplete cell fate decision – one wherein there is persistent
MAPK signaling, AP-1 activation, and IL-33 in the pancreas microenvironment. In vivo, this epigenetic memory
controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased
tumorigenesis with an oncogenic Kras mutation. We have demonstrated that both persistent chromatin and
transcriptional changes constituting memory can be specifically recalled in the response to oncogenic stress.
Together, our findings have defined the dynamics and recall of an epigenetic memory of inflammation that
impacts cell fate decisions.
In this proposal, we focus on building an understanding of the molecular underpinnings of memory of
inflammation. Specifically, we will leverage our lineage-traced mouse models of pancreatic inflammation to
establish an understanding of AP-1 binding to chromatin and its interaction partners (Aim 1). We will also employ
specific genetic and pharmacologic perturbations to AP-1 factors and MAPK signaling in vivo to articulate
whether epigenetic memory is reversible (i.e. inducing epigenetic `amnesia') (Aim 2). Third, we will examine the
role of IL-33 as a cell-extrinsic factor driving the memory phenotype (Aim 3).
Together our studies will define the molecular mechanisms that govern epigenetic memory of inflammation in
the pancreas. In so doing, we expect to uncover the key cell types, transcription factors, and signaling
intermediates that lead to persistent molecular alterations following transient injury. In turn, this work will shed
new light in to how memory can be targeted to abrogate the diminished threshold for tumorigenesis. By analyzing
the rational means for inducing epigenetic `amnesia', we will exploit the therapeutic opportunity that the durability
of epigenetic memory offers to address the ...

## Key facts

- **NIH application ID:** 10982148
- **Project number:** 1R01DK138154-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Rohit Chandwani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $506,546
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982148

## Citation

> US National Institutes of Health, RePORTER application 10982148, Defining the molecular determinants of inflammatory memory in the pancreas (1R01DK138154-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10982148. Licensed CC0.

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