Role of the GPR4 Receptor in Intestinal Inflammation and Cancer

East Carolina University, Greenville NC

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Abstract

? DESCRIPTION (provided by applicant): Tumor development is a complex process significantly influenced by gene mutations and environmental factors. Chronic inflammation, as illustrated in inflammatory bowel disease (IBD), is a crucial risk factor that can predispose susceptible cells to oncogenic transformation, leading to tumor formation. Anti-inflammatory agents have been evaluated for cancer prevention. GPR4 is a pro-inflammatory pH-sensing G protein-coupled receptor (GPCR) that is activated by acidosis, a biochemical hallmark of the microenvironment of inflammatory tissues and tumors. We have recently demonstrated that activation of GPR4 by acidotic stress stimulates the expression of inflammatory genes in vascular endothelial cells (ECs) and also augments leukocyte-EC adhesion. Our preliminary results further demonstrate that GPR4 increases inflammatory responses in a mouse model of inflammatory bowel disease. In this project, we will investigate the role of GPR4 in intestinal inflammation and cancer using GPR4 knockout mice and pharmacological GPR4 inhibitors. We will employ widely accepted protocols using dextran sulfate sodium (DSS) to induce inflammatory bowel disease and using DSS in combination with azoxymethane (AOM) to induce colitis-associated colorectal cancer in wild-type and GPR4 knockout mice and determine how GPR4 deficiency modulates intestinal inflammation and neoplasia. We will also examine the therapeutic effects of the GPR4 inhibitor on regulating intestinal inflammation and carcinogenesis in the IBD mouse model.