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.
Acidosis is an important stress factor involved in a variety of human diseases such as inflammation, cancer, diabetes, ischemia, lung diseases and kidney diseases. We have recently shown that the GPR4 receptor is a functional acid sensor in vascular endothelial cells, and activation of GPR4 by acidosis induces a broad inflammatory response in endothelial cells and enhances endothelial cell-leukocyte adhesion. Here we propose to investigate the role for GPR4 in intestinal inflammation and colitis-associated colorectal cancer. We will also assess the therapeutic value of the small molecule modulators of GPR4 for the treatment and prevention of inflammatory bowel disease and colorectal cancer.
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