# Defining signaling networks in epithelial homeostasis

> **NIH NIH R35** · UNIVERSITY OF ARIZONA · 2022 · $374,598

## Abstract

ABSTRACT
The goal of the work outline in this proposal is to understand the fundamental signaling that controls cell fate to
maintain tissue homeostasis. Epithelial tissues demonstrate an intrinsic ability for their constituent cells to
organize and maintain a steady-state of form and function. Many disease states lack these intrinsic controls.
Epithelial tissues of the human body are in a constant state of renewal. Our understanding of the signaling
systems that control how these complex epithelial tissues maintain robust organization is incomplete. Essential
for progress, we need a quantitative understanding of signaling at the single-cell level in the context of
physiological conditions to reveal systems-level behaviors that can be targeted therapeutically. We focus on
protein kinases as critical mediators of signaling in the cell, which are well known to play prominent roles in
tissue function and drivers of disease. Our kinome-wide studies have identified GSK3 and CLK3 as major
tissue homeostasis regulators that govern the balance between proliferation and differentiation. In Project 1,
we hypothesize GSK3 requires multiple suppressive inputs that uniquely produce different fate outcomes
ranging from stem cells, transit-amplifying, and differentiated. We will provide the first systems-level mapping
for multiple inputs onto GSK3 dynamics and how these dynamics are decoded into distinct cellular outcomes
of renewing epithelium. In Project 2, we hypothesize CLK3 is a gatekeeper controlling stem cell fate through
transcriptome regulation. We will define the activity of CLK3 in the stem cell niche as a regulator of expression
and splicing of Wnt-target genes to promote stemness. Our approach uses high-throughput quantitative
microscopy to measure single-cell behaviors in physiological organoid homeostatic culture models. Our
research will define the regulatory mechanisms for two critical kinases, GSK3 and CLK3, and discover novel
signaling circuitry needed for the accurate organization of renewing and regenerative epithelia, uncovering new
strategies for treating diseases of regenerative tissues.

## Key facts

- **NIH application ID:** 10499880
- **Project number:** 1R35GM147128-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Curtis Andrew Thorne
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,598
- **Award type:** 1
- **Project period:** 2022-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499880

## Citation

> US National Institutes of Health, RePORTER application 10499880, Defining signaling networks in epithelial homeostasis (1R35GM147128-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10499880. Licensed CC0.

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