Enteric Glia, Sexual Dimorphism and GI Motility

肠胶质细胞、性别二态性和胃肠道运动

• 批准号: 9811525
• 负责人: Meenakshi Rao
• 金额: $ 11.05万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-29 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811525
• 关键词: Acute; Adult; Affect; Afferent Neurons; Androgen Receptor; Androgens; Attenuated; Behavior; Biological Assay; Calcium; Castration; Cells; Chemicals; Chronic; Clinical; Constipation; Data; Diarrhea; Digestive System Disorders; Diphtheria Toxin; Disease; Drug Targeting; Dyspepsia; Enteral; Enteric Nervous System; Enterochromaffin Cells; Epithelial; Esthesia; Estradiol; Estrogens; Exhibits; Exposure to; Female; Fetal Development; Functional Gastrointestinal Disorders; Functional Imaging; Functional disorder; Gastroenterology; Gastrointestinal Motility; Genes; Genetic Models; Gonadal Hormones; Gonadal Steroid Hormones; Human; Image; Immunity; Inflammation; Intestines; Irritable Bowel Syndrome; K-Series Research Career Programs; Label; Learning; Light; Limb structure; Maintenance; Measures; Mediating; Molecular; Mucous Membrane; Mus; Nerve; Nervous System Physiology; Neuraxis; Neurobiology; Neuroglia; Neurons; Neurosciences; Neurotransmitters; Operative Surgical Procedures; Pathway interactions; Patients; Peristalsis; Permeability; Pharmaceutical Preparations; Play; Population; Prevalence; Principal Investigator; Proteins; Proteolipids; Reflex action; Regulation; Research; Role; Series; Serotonin; Serotonin Receptors 5-HT-3; Sex Characteristics; Sex Functioning; Signal Transduction; Stanolone; Symptoms; Techniques; Testing; Testosterone; Therapeutic; Training; Treatment Efficacy; Visceral; Woman; biological adaptation to stress; calcium indicator; cell motility; chronic abdominal pain; design; effective therapy; ex vivo imaging; experience; experimental study; extracellular; gastrointestinal; gastrointestinal function; gastrointestinal infection; gut-brain axis; in vivo; insight; male; men; new technology; new therapeutic target; novel; paracrine; personalized medicine; personalized therapeutic; programs; promoter; receptor; serotonin receptor; serotonin transporter; sex; sexual dimorphism; skills; therapeutic target; treatment response; uptake; virtual

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.

项目摘要 功能性胃肠道（GI）疾病，例如慢性便秘，功能性消化不良和肠易激 综合征（IBS）高度普遍，但几乎没有明确的治疗方法。仅IBS就会影响超过10％ 美国人群，导致慢性腹痛并改变了胃肠道运动，导致腹泻和/或 便秘。 IBS已注意到重大的性别差异。男人和女人经常出现不同的 症状和对治疗的反应不同。识别这些性别的基本基础 差异将导致对IBS的更有效和个性化治疗。肠神经系统（ENS）， 由肠道内在神经回路组成，对于调节胃肠道运动至关重要。细胞 ENS的分子或电路级别的性别差异可能是IBS的性别差异，但这不是 经过深入研究。我们有证据表明，胶质细胞（ENS的非神经元细胞）中的功能障碍导致 对结肠运动的性二态作用，以及肠神经胶质对性激素的表达受体。这 因此，该项目的研究目标是确定：（1）持续暴露于性腺性激素， 例如睾丸激素和雌激素，调节结肠运动性，（2）神经胶质如何与内在感觉相互作用 ENS中的神经元以性别依赖性的方式调节结肠运动。在这五年的过程中 职业发展奖，首席调查员将在她以前的临床培训基础上 胃肠病学以及她在神经科学方面的强大研究背景，以获得学习性的新技能 ENS的差异和适应新技术来测量肠中的神经元活性。这些 技能将应用于小鼠遗传模型中的一系列体内和体内实验， 旨在检验以下假设，即ENS内神经元 - 胶体相互作用中的性二态性是性别构成的 胃肠道运动和功能疾病的差异。该项目的成功完成将为 胃肠道运动性别差异的细胞机制，并为主要研究者提供培训和 经验她需要启动肠神经生物学独立研究计划。