Project 175659

Inflammatory bowel disease (IBD) is increasingly prevalent and approximately 10,000 new cases are diagnosed in Canada every year. While the underlying mechanisms causing IBD are unknown, recent advances demonstrate that the enteric nervous system (ENS) plays a key role. In the central nervous system (CNS), glial cells are critical mediators of inflammation. During pathological conditions, astrocytes and microglia release excitatory amino acids, ATP, and proinflammatory cytokines such as interleukin-1β through ionotropic purinergic P2X7 receptors (P2X7Rs), causing proinflammatory responses, neurodegeneration, and the development of chronic and neuropathic pain. Like CNS neurons, enteric neurons are surrounded and far outnumbered by a distinct type of peripheral glial cell called enteric glia. Molecular and morphological similarities between enteric glia and CNS astrocytes suggest they fulfill similar roles but the functional role of enteric glia remains largely unknown, although enteric glia have been implicated in the development of intestinal inflammation. We recently discovered that enteric glia are actively involved in purinergic neurotransmission in the ENS. Enteric glia express P2X7Rs but their role in the development of inflammatory conditions in the ENS is unknown. We propose that enteric glia upregulate P2X7R function during inflammation, leading to excitotoxicity in enteric neurons. We will test this hypothesis using calcium imaging and dye uptake assays to investigate if enteric glial P2X7Rs are more functional in inflamed intestines. Further, we will utilize mice deficient in the P2X7 gene (P2X7-KO) and mice administered inhibitors of P2X7Rs to test if modulation of P2X7Rs prevents inflammation-induced neuronal loss. The proposed experiments will significantly add to our comprehension of cellular mechanisms leading to IBD, leading to the development of targeted pharmaceuticals for IBD and increasing the quality of life for thousands of Canadians.