# The role of Paneth cell sirtuin 1 in intestinal tissue homeostasis and colorectal carcinogenesis.

> **NIH NIH FI2** · U.S. NATIONAL INST OF ENVIRON HLTH SCIS · 2021 · —

## Abstract

Project Summary
Colorectal cancer (CRC) represents the third most diagnosed malignancy in the world (1). More than two-fold of
all cases and deaths are associated with modifiable environmental risk factors (2). In particular, CRC incidence
has been increasing at younger ages (<50 years) (3). Therefore, novel target-based approaches that link both
genetic and environmental factors need to be established for the treatment of this neoplasm (4, 5). Intestinal
epithelial homeostasis is maintained by a complex interplay between epithelial cells, gut microorganisms, and
immune cells (6, 7). Disruptions of these orchestrated interactions results in inflammatory disorders such as
colitis and CRC. One genetic factor that modulates the interactions between gut epithelium, microbiota and
immune cells is sirtuin 1 (SIRT1), the most conserved mammalian member of a family of highly conserved NAD+-
dependent histone deacetylases and/or ADP-ribosyltransferases called sirtuins (8). We and others have shown
that intestinal epithelial SIRT1 regulates intestinal stress response and tissue homeostasis, deficiency of this
factor leads to intestinal inflammation, disruption of gut microbial composition, and altered susceptibility to
environmentally CRC (9-13). Particularly, we found that deletion of intestinal epithelial SIRT1 results in
hyperactivation of Paneth cells (11), intestine-originated innate immune cells important for gut microbiota
regulation and intestinal stem cell niche maintenance (14). Recently we generated a Paneth-cell specific SIRT1
KO mouse model (SIRT1 PKO) by breeding SIRT1 floxed allele with Defa6-Cre line (15), and found elevated
expression of Paneth cell markers, increased Paneth cell number, and enhanced protection against chemical
induced inflammation.
This study will investigate the role of SIRT1 in Paneth cells and how deficiency of SIRT1 in Paneth cells impacts
environmental influences on intestinal epithelial homeostasis. Since gut microbiota plays a fundamental role on
the host immune system (16), as well as the efficacy of anti-tumor immunotherapies (17-20), it will also seek to
parse out SIRT1 regulation of gut microbiome and how this interaction can alter intestinal and systemic immune
function, which can impact anti-tumor immunity and the efficacy of anti-tumor immunotherapies. Thus,
understanding the role of SIRT1 in intestinal epithelial in the context of Paneth cells will shed light on to how
disruptions on Paneth cells can result in changes of gut microbiome, altered immune functions, and disrupts
epithelial homeostasis.
The aims of the study are:
Aim 1: To determine if SIRT1 deletion in Paneth cells disrupts gut microbiota and alters gut immunity.
Aim 2: To explore if SIRT1 deletion in Paneth Cells alters anti-tumor immunity.
Aim 3: To investigate if the differential anti-tumor immunity in Flox and PKO mice affects the efficacy of anti-
tumor immunotherapies.

## Key facts

- **NIH application ID:** 10275273
- **Project number:** 1FI2GM143339-01
- **Recipient organization:** U.S. NATIONAL INST OF ENVIRON HLTH SCIS
- **Principal Investigator:** Liz Garcia-Peterson
- **Activity code:** FI2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10275273

## Citation

> US National Institutes of Health, RePORTER application 10275273, The role of Paneth cell sirtuin 1 in intestinal tissue homeostasis and colorectal carcinogenesis. (1FI2GM143339-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10275273. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*