# Mechanisms of cell death and autophagy in intestinal epithelial cells in inflammation and cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $387,731

## Abstract

SUMMARY
Intestinal epithelial cells (IECs) play an important role as barrier and as cellular factories in charge of absorbing
and processing dietary nutrients, as well as the secretion of defense molecules and the orchestration of immune
responses. Alterations in the normal function of IECs contribute to pathologies like inflammatory bowel diseases
(IBD). Importantly, patients with IBD are at an increased risk for colorectal cancer (CRC), which is one of the
most prevalent neoplasias among the US population. Recent studies have shown the critical role of Paneth cell
dysfunction in controlling IEC survival and the etiopathogeneis of intestinal inflammation. Therefore,
understanding how different signaling cascades control intestinal homeostasis is a fundamental question in
biology with potential therapeutic implications for IBD and CRC. We will address these questions in the context
of PKCλ/ι. Our preliminary data demonstrate that the selective inactivation of PKCλ/ι in IECs results in the loss
of Paneth cells, which provokes the break of the intestinal barrier, dysbiosis, intestinal inflammation and
increased tumorigenesis. Importantly, PKCλ/ι expression decreases with progression in CD and it predicts poor
survival in CRC. Of note, this Paneth cell defect is associated with increased crypt apoptosis, JNK activity and
autophagy in PKCλ/ι-deficient IECs. Our hypothesis is that PKCλ/ι is an essential regulator of autophagy and
cell death in intestinal cell homeostasis and inflammation-driven tumorigenesis. In this proposal we will address
the following fundamental questions: (1) What is the role in vivo of JNK activation by PKCλ/ι deficiency in
increased apoptosis of IECs and intestinal inflammation and tumorigenesis? (2) What are the mechanisms
whereby PKCλ/ι inhibits JNK activity? (3) Is enhanced autophagy in PKCλ/ι-deficient IECs a survival
mechanism in vivo to antagonize the increased JNK and apoptosis promoted by the loss of PKCλ/ι and to
prevent intestinal inflammation and tumorigenesis? (4) What are the mechanisms whereby PKCλ/ι represses
autophagy? Questions 1 and 2 will be answered by the experiments described in Aim 1; and questions 3 and 4
will be answered by the experiments described in Aim 2. This proposal will unveil a new paradigm whereby
PKCλ/ι controls IEC apoptosis and autophagy and their role in intestinal homeostasis and inflammation-driven
tumorigenesis, opening possibilities for new therapies.

## Key facts

- **NIH application ID:** 9879706
- **Project number:** 7R01CA207177-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Jorge Moscat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,731
- **Award type:** 7
- **Project period:** 2017-03-21 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879706

## Citation

> US National Institutes of Health, RePORTER application 9879706, Mechanisms of cell death and autophagy in intestinal epithelial cells in inflammation and cancer (7R01CA207177-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879706. Licensed CC0.

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