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Role for myeloid acid ceramidase in colon inflammation and cancer

髓样酸性神经酰胺酶在结肠炎症和癌症中的作用

基本信息

批准号：
10593982
负责人：
Ashley J. Snider
金额：
$ 33.21万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593982
关键词：
Acute Anti-Inflammatory Agents Apoptosis Attenuated Azoxymethane Biological Bone Marrow Cells Ceramidase Ceramides Chronic Circulation Clinical Clinical Research Colitis Colon Colon Carcinoma Colonic inflammation Complex Data Development Disease Enzymes Epithelial Cells Epithelium Future Goals Human Immune Incidence Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Interleukin-10 Knockout Mice Laboratories Lipids Macrophage Malignant Neoplasms Mediating Metabolism Modality Modeling Molecular Mus Myelogenous Myeloid Cells Pathology Pathway interactions Play Publishing Rag1 Mouse Role Sodium Dextran Sulfate Sphingolipids Sphingosine Spontaneous colitis Stimulus Testing Therapeutic Tissues Translating Treatment-Related Cancer Work cell motility chemically induced colitis chemokine colitis associated cancer conditional knockout cytokine design dextran sulfate sodium induced colitis galactosylgalactosylglucosylceramidase immune cell infiltrate immunoregulation in vivo inhibitor lipid metabolism mouse model murine colitis new therapeutic target novel novel therapeutics pharmacokinetics and pharmacodynamics pharmacologic physiologic model recruit response sphingosine 1-phosphate targeted treatment therapeutic development therapeutic target tumor tumorigenesis

项目摘要

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.

生物活性脂质，如神经酰胺及其下游代谢产物，鞘氨醇和鞘氨醇-1-磷酸