Enteric Glia, Sexual Dimorphism and GI Motility

项目摘要 功能性胃肠疾病，如慢性便秘、功能性消化不良和肠易激 综合征(IBS)非常普遍，但几乎没有明确的治疗方法。仅IBS就影响了超过10%的 美国人，引起慢性腹痛和胃肠动力改变，导致虚弱的腹泻和/或 便秘。IBS患者存在显著的性别差异；男性和女性通常表现出不同的 症状并对治疗表现出不同的反应。确定这些性行为的潜在基础 差异将导致对IBS更有效和个性化的治疗。肠道神经系统(ENS)， 它由肠道的内源性神经回路组成，对调节胃肠动力是必不可少的。蜂窝， ENS中分子或回路水平的性别差异可能是IBS性别差异的基础，但这并不是 已经做了很好的研究。我们有证据表明，神经胶质细胞的功能障碍导致脑神经核的非神经细胞 性二型性对结肠运动的影响，以及肠道神经胶质细胞表达性激素受体。这个 因此，该项目的研究目标是确定：(1)如何持续暴露于性腺激素， 如睾丸激素和雌激素，调节结肠运动，以及(2)神经胶质细胞如何与内在感觉相互作用 ENS中的神经元以性别依赖的方式调节结肠运动。在这5年中 职业发展奖，首席研究员将在她之前的临床培训的基础上 胃肠病学以及她在神经科学方面的强大研究背景，在研究性方面获得了新的技能 ENS的差异和采用新技术来测量肠道中的神经元活动。这些 这些技术将应用于一系列体内和体外的小鼠遗传模型实验，这些实验包括 旨在验证这样一种假设，即神经元-神经胶质细胞相互作用中的性别二型性是性别的基础 胃肠动力与功能性疾病的差异。这一项目的顺利完成将给我们带来新的启示 胃肠道运动的性别差异的细胞机制，并为首席研究员提供培训和 她需要启动她在肠道神经生物学方面的独立研究计划。

Project Summary Functional gastrointestinal (GI) disorders such as chronic constipation, functional dyspepsia and irritable bowel syndrome (IBS) are highly prevalent but have few definitive treatments. IBS alone affects more than 10% of the U.S. population, causing chronic abdominal pain and altered GI motility leading to debilitating diarrhea and/or constipation. Prominent sex differences have been noted in IBS; men and women often present with different symptoms and exhibit different responses to treatment. Identifying the underlying basis of these sex differences will lead to more effective and personalized treatments for IBS. The enteric nervous system (ENS), which consists of the intrinsic nerve circuits of the bowel, is essential for regulating GI motility. Cellular, molecular, or circuit-level sex differences in the ENS may underlie sex differences in IBS, but this has been not been well studied. We have evidence that dysfunction in glial cells, the non-neuronal cells of the ENS, leads to a sexually dimorphic effect on colonic motility, and that enteric glia express receptors for sex hormones. The research objectives of this project are thus to determine: (1) how ongoing exposure to gonadal sex hormones, such as testosterone and estrogen, regulates colonic motility, and (2) how glia interact with intrinsic sensory neurons in the ENS to regulate colonic motility in a sex-dependent manner. Over the course of this 5 year career development award, the principal investigator will build upon her previous clinical training in gastroenterology as well as her strong research background in neuroscience, to gain new skills in studying sex differences in the ENS and adapting novel technologies to measuring neuronal activity in the bowel. These skills will be applied to a series of in vivo and ex vivo experiments in mouse genetic models, which are designed to test the hypothesis that sexual dimorphism in neuron-glia interactions within the ENS underlies sex differences in GI motility and functional disease. Successful completion of this project will shed new light on cellular mechanisms of sex differences in GI motility, and provide the principal investigator with the training and experience she needs to launch her independent research program in enteric neurobiology.