The role of enteric glia in visceral hypersensitivity

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PROJECT SUMMARY The proposed training and research plans are focused on developing the Applicant’s expertise in enteric neuroscience and pain signaling. To this end, the training plan focuses on a mix of comprehensive technical research and career development training with the goal of providing the Applicant a complete set of skills necessary to develop into an independent scientist. The research plan complements the training experience by investigating mechanisms whereby enteric glia regulate the activity of visceral nociceptive neurons. The proposed research will test the central hypothesis that enteric glia promote nociceptor hypersensitivity during acute inflammation through mechanisms that include connexin 43-dependent release of prostaglandin E2 (PGE2), the regulation of monoglyceride lipase (MAGL), and sensitization of transient-receptor potential vanilloid-1 (TRPV1) channels in nociceptive nerve terminals. This hypothesis will be tested in two Specific Aims that utilize advanced dual chemo- and optogenetic reporter systems in mice, advanced cellular imaging assays, and whole animal models. Aim 1 will study enteric glial mechanisms that modulate nociceptor activity during acute inflammation through connexin 43-dependent PGE2 release. Aim 2 will study how glial MAGL contributes to nociceptor sensitization during acute inflammation. The applicant will develop knowledge in cellular imaging, enteric neurobiology, and pain signaling through hands-on research, coursework, and expert mentorship. The major impact of the proposed research and training is to provide a significant enhancement of the applicant’s expertise in cutting-edge skills and technologies in neuroscience and physiology, while simultaneously defining novel mechanism that contribute to visceral pain that will contribute to the advancement of novel therapies.