# Cellular and molecular mechanisms of cigarette smoking-induced Paneth cell abnormality

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $354,375

## Abstract

ABSTRACT
One of the challenges for the management of Crohn’s disease (CD; a chronic intestine inflammatory disorder)
is to develop more efficient and personalized treatment strategies. A major reason why CD is difficult to treat is
because the disease is induced by both genetic susceptibility and environmental factors. Understanding how
CD-relevant gene-environment interaction affects disease outcome will inform the development of therapeutic
strategies. We showed that the morphologic phenotype and function of small intestinal Paneth cells are
modifiable by integrated effects from both host genetics and known CD environmental risk factor, such that CD
patients (and corresponding genetic modified mice) who harbor ATG16L1 T300A polymorphism when exposed
to cigarette smoking (a key CD risk factor) develop Paneth cell abnormality. However, the cellular and
molecular mechanisms of cigarette smoking-induced Paneth cell abnormality are unknown. Our long-term goal
is to dissect the cellular and molecular mechanisms of how gene-environment interactions affect the
development and outcome of Crohn’s disease. These discoveries will facilitate design of therapy trials for CD.
The objective of this grant is to determine how cigarette smoking induces Paneth cell abnormality. The central
hypothesis is that both Paneth cell-intrinsic and –extrinsic factors collectively contribute to smoking-induced
Paneth cell defects. Our rationale is that identification of the mechanism(s) to restore Paneth cell function will
offer new therapeutic opportunities for CD. Our specific aims will test the following hypotheses: (Aim1)
Autophagy induction rescues smoking-induced Paneth cell abnormality; (Aim 2) Intestinal macrophages are
activated by cigarette smoking, which in turn triggers Paneth cell apoptosis. Upon conclusion, we will
understand the role for autophagy and intestinal macrophages in modulating Paneth cell function. This
contribution is significant since it will establish autophagy induction as a new intervention strategy for CD
patients with Paneth cell abnormality. The proposed research is innovative because we investigate the effect of
autophagy signaling pathways on defective Paneth cells, a heretofore-unexamined process. We also use
state-of-the-art intestinal stem cell culture system to identify molecular and cellular targets that affect Paneth
cell functions. Identifying the mechanisms of how gene-environment interactions regulate a key disease-
relevant cellular phenotype will provide insight into other inflammatory disorders.

## Key facts

- **NIH application ID:** 10026985
- **Project number:** 1R01DK125296-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ta-Chiang Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,375
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026985

## Citation

> US National Institutes of Health, RePORTER application 10026985, Cellular and molecular mechanisms of cigarette smoking-induced Paneth cell abnormality (1R01DK125296-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10026985. Licensed CC0.

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