Enteric Glia, Sexual Dimorphism and GI Motility

项目摘要 功能性胃肠道（GI）疾病，如慢性便秘、功能性消化不良和肠易激惹 肠易激综合征（IBS）非常普遍，但很少有明确的治疗方法。IBS单独影响超过10%的 美国人群，引起慢性腹痛和胃肠道动力改变，导致衰弱性腹泻和/或 便秘在IBS中已经注意到了显著的性别差异;男性和女性经常表现出不同的 症状和表现出不同的反应治疗。确定这些性别的潜在基础 差异将导致更有效和个性化的治疗IBS。肠神经系统（ENS）， 其由肠的内在神经回路组成，对于调节GI运动是必需的。细胞， ENS的分子或电路水平的性别差异可能是IBS性别差异的基础，但这并不是 被好好研究过了。我们有证据表明，神经胶质细胞（ENS的非神经元细胞）的功能障碍会导致 对结肠运动的性二态效应，以及肠神经胶质表达性激素受体。的 因此，该项目的研究目标是确定：（1）持续暴露于性腺性激素， 如睾丸激素和雌激素，调节结肠运动，以及（2）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，主要研究者将建立在她以前的临床培训， 胃肠病学以及她在神经科学方面的强大研究背景，以获得研究性的新技能 ENS的差异，并采用新技术来测量肠道中的神经元活动。这些 技能将应用于一系列在小鼠遗传模型中的体内和体外实验， 旨在检验ENS内神经元-神经胶质相互作用中的性二态性是性别的基础这一假设 胃肠道运动和功能性疾病的差异。该项目的成功完成将为我们提供新的信息， GI运动性别差异的细胞机制，并为主要研究者提供培训和 她需要的经验来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.