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.

项目概要 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）非常普遍，但几乎没有明确的治疗方法。仅 IBS 就影响超过 10% 美国人口，引起慢性腹痛和胃肠道运动改变，导致虚弱性腹泻和/或 便秘。 IBS 中存在显着的性别差异；男人和女人经常以不同的方式出现 症状并对治疗表现出不同的反应。确定这些性别的根本基础 差异将导致更有效和个性化的IBS治疗。肠神经系统（ENS）， 它由肠道的内在神经回路组成，对于调节胃肠道运动至关重要。蜂窝， ENS 中的分子或回路水平性别差异可能是 IBS 性别差异的基础，但这并没有被证实。 得到了很好的研究。我们有证据表明神经胶质细胞（ENS 的非神经元细胞）功能障碍会导致 对结肠运动的性别二态性影响，并且肠神经胶质细胞表达性激素受体。这 因此，该项目的研究目标是确定：（1）如何持续接触性激素， 例如睾酮和雌激素，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性方式调节结肠运动。在这5年的时间里 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，以获得研究性的新技能 ENS 的差异以及采用新技术来测量肠道神经元活动。这些 技能将应用于小鼠遗传模型的一系列体内和离体实验，这些实验是 旨在检验 ENS 内神经元-胶质细胞相互作用的性别二态性是性别基础的假设 胃肠道运动和功能性疾病的差异。该项目的顺利完成将给我们带来新的认识 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 她需要丰富的经验来启动肠神经生物学的独立研究项目。