# Cytoprotective pathways in esophageal squamous epithelia

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $559,924

## Abstract

PROJECT SUMMARY
Disorders of the esophagus are significant health problems in the U.S. and throughout the world, and
esophageal cancer, of which more than 80% is esophageal squamous cell cancer (ESCC), is the 6th most
common cause of cancer death worldwide. Exposure of esophageal squamous epithelial cells (keratinocytes)
to injurious agents such as cigarette smoke and alcohol predisposes to ESCC, and yet malignant
transformation of a single esophageal keratinocyte even in response to such stressors is rare. Thus, important
cytoprotective mechanisms must exist in normal esophageal keratinocytes to respond to these insults and
prevent malignant transformation of these cells. To date, these mechanisms are not well understood. Here,
we propose to delineate important cytoprotective pathways in esophageal keratinocytes, focusing on the key
transcriptional regulator Krüppel-like factor 5 (KLF5) and the tumor suppressor p53 in the response to
physiologic stress. In normal epithelia, KLF5 functions to promote proliferation and migration and to inhibit
inflammation, and in new preliminary data, we define critical functions for KLF5 and wild-type p53 in the cellular
responses to exogenous stress in non-transformed esophageal keratinocytes and demonstrate that mutant
p53 modulates genome-wide binding of KLF5, thereby altering the targets and pathways governed by KLF5 in
this context. Our overarching hypothesis is that KLF5 and p53 are a molecular rheostat, coordinately
regulating esophageal squamous epithelial responses to exogenous stressors, and that disruption of this
regulation underlies defective cell repair and ESCC. To test this hypothesis, we will pursue the following
interrelated Specific Aims: 1. We will define KLF5-p53 targets and function in normal keratinocytes with
exogenous stress; 2. We will determine mutant p53 alterations of genome-wide KLF5 binding in homeostasis
and stress; 3. We will delineate the functions of KLF5 and p53 in esophageal mucosal injury resulting from
smoking and alcohol. Overall, the proposed studies provide a framework to understand the mechanisms by
which normal esophageal keratinocytes respond to environmental stresses and the perturbations of these
responses that underlie malignant transformation and progression in the squamous esophagus.

## Key facts

- **NIH application ID:** 10888225
- **Project number:** 5R01DK120989-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JONATHAN P KATZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $559,924
- **Award type:** 5
- **Project period:** 2023-07-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888225

## Citation

> US National Institutes of Health, RePORTER application 10888225, Cytoprotective pathways in esophageal squamous epithelia (5R01DK120989-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10888225. Licensed CC0.

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