# Role for myeloid acid ceramidase in colon inflammation and cancer

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $332,080

## Abstract

Bioactive lipids, such as ceramide and its downstream metabolites, sphingosine, and sphingosine-1-phosphate
(S1P), mediate critical biologic responses, including inflammation and cancer1. Thus, the enzymes regulating
lipid metabolism are intriguing therapeutic targets. The long-term goal of this project is to define the role of the
bioactive sphingolipid metabolizing enzyme, acid ceramidase (AC), in colitis and colitis-associated cancer (CAC)
and determine whether targeting this enzyme could serve as a novel anti-inflammatory/anti-CAC therapy.
 The PI’s laboratory has an established track record of expertise in sphingolipid metabolism and function2,3.
Our recent work has begun to uncover a specific and very unique role for myeloid (Mye) AC in colitis and CAC.
Using dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced CAC in murine
models, we found that AC expression is increased in the inflammatory infiltrate but not in the colon epithelium.
Similarly, we observed increased AC expresion in tissue macrophages in humans with colitis and colon cancer.
In conditional knockout mice deletion of AC in myeloid cells, (Mye AC cKO), but not intestinal epithelial cells,
decreased immune infiltrate and protected mice from colitis and CAC. Moreover, we found that our AC-specific
inhibitor, LCL521, attenuates inflammation in a chronic colitis model (IL10 deficient mice). Finally, our newest
preliminary data using bone marrow derived macrophages (BMDMs) from Mye AC cKO mice strongly hint that
Mye AC may be required for inflammatory responses in these cells. Together these data suggest that Mye AC
plays a large role the development of colitis and CAC.
 Based on our substantial preliminary data, we hypothesize that loss of Mye AC activity is protective against
colitis and CAC by modulating colonic inflammatory infiltrate, and that targeting Mye AC may result in novel
disease-modifying therapy in colitis and CAC. This hypothesis will be tested by the following Specific Aims:
Specific Aim 1. Establish that Mye AC cKO protects from chronic colitis and CAC in vivo.
Specific Aim 2. Determine the mechanisms by which loss of Mye AC protects from chronic colitis in vivo
and probe these mechanisms in cells.
Specific Aim 3. Advance pharmacologic inhibition of AC as a novel colitis and CAC target.
The significance of these studies lies in the unique role of AC as the ceramidase that is clearly important in colitis
and CAC, and the potential for AC as a novel therapeutic target. Identifying the mechanisms by which AC
regulates chronic colitis and CAC, with specific focus on Mye AC, is a crucial first step in the design of novel
therapies targeting this pathway. In addition, the studies that target AC in specific mouse models of colitis and
CAC, will allow us to begin to translate our studies into clinical therapeutic approaches in the very near future.

## Key facts

- **NIH application ID:** 10418031
- **Project number:** 1R01DK132079-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Ashley Jones Snider
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $332,080
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418031

## Citation

> US National Institutes of Health, RePORTER application 10418031, Role for myeloid acid ceramidase in colon inflammation and cancer (1R01DK132079-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10418031. Licensed CC0.

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