# Cellular Determinants of AH Receptor Signaling

> **NIH NIH R01** · UNIVERSITY OF MEMPHIS · 2024 · $362,500

## Abstract

PROJECT SUMMARY
The long-term goal of this project is to understand the role of the aryl hydrocarbon receptor (AHR) in the
regulation of the function and homeostasis of the skin epidermal permeability barrier. In this project we will
expand on our discovery that the AHR regulates keratinocyte differentiation by controlling metabolic
reprogramming and test the hypothesis that differences in the ligand-directed metabolomes moderate the
balance between toxic and therapeutic AHR ligands. Past project periods of this application have focused on
understanding the mechanisms of action that result in the skin toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) and other environmental pollutants that work through the AHR. In 2022, tapinarof (TAP) was approved
as the first therapeutic AHR ligand for treatment of psoriasis. This application proposes to leverage the
differences in the actions of these AHR ligands to explore their distinct programs of metabolic reprogramming,
contributing to their respective metabolomes and their actions on the skin. In preliminary studies we identified
lipid biosynthesis and metabolism as major components of AHR-regulated metabolic reprogramming. Using
lipidomic analyses, we found differences in key bioactive lipids of the lipidomes of TCDD and TAP that differ in
pro- and anti-inflammatory activities. To test our hypothesis that differences in the ligand-directed
metabolomes moderate the balance between disease-promoting (“Toxic”) and health-promoting
(“Therapeutic”) AHR ligands, we propose three aims. 1) Define the ligand-directed metabolomes of TCDD and
TAP, cataloging common and divergent lipidomes and their bioactive lipids; 2) Determine the modulatory
effects of TCDD and TAP on human keratinocyte models of psoriasis; 3) Identify the key bioactive lipid
pathways of TCDD and TAP in mouse epidermis and determine their roles in ligand modulation of imiquimod-
induced psoriasiform lesions. Findings from these studies will advance the fundamental understanding of the
molecular responses to ligand activation of the keratinocyte AHR and the physiological processes of the
epidermis that are affected in a ligand-selective manner.

## Key facts

- **NIH application ID:** 10882722
- **Project number:** 2R01ES017014-11A1
- **Recipient organization:** UNIVERSITY OF MEMPHIS
- **Principal Investigator:** THOMAS R SUTTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $362,500
- **Award type:** 2
- **Project period:** 2010-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882722

## Citation

> US National Institutes of Health, RePORTER application 10882722, Cellular Determinants of AH Receptor Signaling (2R01ES017014-11A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10882722. Licensed CC0.

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