The role of enteric glia in visceral hypersensitivity

项目总结 拟议的培训和研究计划侧重于发展申请者在肠道方面的专业知识 神经科学和疼痛信号。为此目的，培训计划侧重于综合技术组合 研究和职业发展培训，目的是为申请者提供一整套技能 成为一名独立的科学家所必需的。研究计划通过以下方式补充培训经验 探讨肠神经胶质细胞调节内脏伤害性神经元活动的机制。这个 拟议中的研究将检验肠神经胶质细胞促进伤害性感受器超敏反应的中心假设 依赖缝隙连接蛋白43释放前列腺素E_2的急性炎症机制 前列腺素E_2(PGE_2)、单甘酯脂肪酶(MAGL)的调节和瞬时受体电位的敏化 伤害性神经末梢的香草素-1(TRPV1)通道。这一假设将在两个具体目标中得到检验 在小鼠身上使用先进的化学和光遗传双重报告系统，先进的细胞成像分析， 以及完整的动物模型。目标1将研究肠道神经胶质调节伤害性感受器活动的机制 通过依赖缝隙连接蛋白43的PGE2释放引起急性炎症。Aim 2将研究胶质MAGL如何贡献 在急性炎症期间伤害性感受器敏化。申请者将发展细胞成像方面的知识， 肠道神经生物学，以及通过动手研究、课程作业和专家指导发出疼痛信号。这个 拟议的研究和培训的主要影响是显著提高申请人的 在神经科学和生理学方面的前沿技能和技术方面的专业知识，同时定义 有助于内脏疼痛的新机制，这将有助于新疗法的进步。

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.