The role of enteric glia in visceral hypersensitivity

项目摘要 拟议的培训和研究计划的重点是发展申请人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培训， 研究和职业发展培训，旨在为申请人提供一整套技能 成为一名独立的科学家。研究计划通过以下方式补充培训经验： 研究肠神经胶质细胞调节内脏伤害感受神经元活性的机制。的 拟议的研究将测试中心假设，肠胶质细胞促进伤害感受器超敏反应， 通过连接蛋白43依赖性释放前列腺素E2等机制引起的急性炎症 前列腺素E2（PGE 2）、单甘脂酶（MAGL）的调节和瞬时受体电位的致敏 在伤害性神经末梢中的香草素-1（TRPV 1）通道。这一假设将在两个具体目标中得到检验 在小鼠中利用先进的双重化学和光遗传学报告系统，先进的细胞成像测定， 和整个动物模型。目的1将研究肠神经胶质细胞的机制，调节伤害性感受器的活动， 急性炎症通过连接蛋白43依赖性PGE 2释放。目标2将研究胶质细胞MAGL如何促进 与急性炎症时伤害感受器的敏感性有关。申请人将发展细胞成像方面的知识， 肠神经生物学，并通过动手研究，课程和专家指导疼痛信号。的 拟议的研究和培训的主要影响是提供申请人的显着提高 在神经科学和生理学的尖端技能和技术的专业知识，同时定义 新的机制，有助于内脏疼痛，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.