PURINERGIC NEUROGENIC MUCOSAL SECRETION

嘌呤能神经源性粘膜分泌

• 批准号: 6814299
• 负责人: JACKIE D WOOD
• 金额: $ 29.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6814299
• 关键词: Xenopus; adenosine triphosphate; calcium flux; electrophysiology; enteric nervous system; gastrointestinal epithelium; guinea pigs; in situ hybridization; intracellular transport; membrane potentials; molecular cloning; neural transmission; neuroendocrine system; neurons; neuropharmacology; point mutation; purinergic receptor; receptor expression; secretion; tissue /cell culture; transfection /expression vector; vasoactive intestinal peptide; voltage /patch clamp

DESCRIPTION (provided by applicant): The overall aim of this project is to characterize a novel purinergic slow excitatory postsynaptic potential (EPSP) that is mediated by a metabotropic ATP receptor (P2Y1 receptor) in the enteric nervous system. Evidence for the existence of the purinergic slows EPSP emerged from pilot studies in which the P2Y1 receptor antagonist MRS2179 selectively blocked both the slow EPSP and slow EPSP-like responses evoked by ATP in submucosal neurons. The hypothesis that the purinergic slow EPSP is mediated by synaptic release of ATP and P2Y1 receptors in submucosal secretomotor neurons will be tested pharmacologically in morphologically identified neurons. Molecular cloning and functional expression will be used to better characterize the P2Y1 receptor. The proposal emerged from pilot/feasibility results, which suggest the hypothesis that intestinal secretomotor neurons receive purinergic slow excitatory synaptic input from neurons in the myenteric plexus, from neighboring neurons in the submucosal plexus and from sympathetic neurons in prevertebral ganglia. Added support for the hypothesis came from the discovery that the selective P2Y1 receptor antagonist MRS2179 suppressed neurogenic secretory responses evoked by application of ATP and by transmural electrical stimulation of secretomotor neurons in Ussing chamber experiments. Fulfilling the aims of this proposal will lead to better understanding of the role of a newly discovered purinergic slow EPSP in the enteric nervous system at the cellular, molecular and integrated system levels. The pilot/feasibility data are the first to demonstrate a functional purinergic slow EPSP in the enteric nervous system. The discovery that a P2Y1 receptor mediates the slow EPSP in intestinal secretomotor neurons might help in development of new drugs for treatment of the irritable bowel syndrome, inflammatory bowel disease and other disorders of defecation by targeting the P2Y1 receptor or ATP metabolic pathways in the pool of enteric neurons that control intestinal secretion.

描述（由申请人提供）：该项目的总体目标是表征一种新型嘌呤能慢兴奋性突触后电位（EPSP），该电位由肠神经系统中的代谢型 ATP 受体（P2Y1 受体）介导。 嘌呤能减慢 EPSP 存在的证据来自初步研究，其中 P2Y1 受体拮抗剂 MRS2179 选择性阻断粘膜下神经元中 ATP 引起的慢 EPSP 和慢 EPSP 样反应。 嘌呤能慢 EPSP 是由粘膜下分泌运动神经元中 ATP 和 P2Y1 受体的突触释放介导的假设将在形态学鉴定的神经元中进行药理学测试。 分子克隆和功能表达将用于更好地表征 P2Y1 受体。 该提议源于试点/可行性结果，该结果表明肠道分泌运动神经元接收来自肌间神经丛中的神经元、粘膜下神经丛中的邻近神经元和椎前神经节中的交感神经元的嘌呤能缓慢兴奋性突触输入。 这一假设的进一步支持来自于以下发现：选择性 P2Y1 受体拮抗剂 MRS2179 抑制了尤斯室实验中应用 ATP 和分泌运动神经元的跨壁电刺激所引起的神经源性分泌反应。 实现该提案的目标将有助于在细胞、分子和集成系统水平上更好地理解新发现的嘌呤能慢 EPSP 在肠神经系统中的作用。 试点/可行性数据首次证明了肠神经系统中具有功能性嘌呤能慢 EPSP。 P2Y1 受体介导肠道分泌运动神经元中缓慢 EPSP 的发现可能有助于开发新药，通过靶向 P2Y1 受体或 ATP 代谢途径来治疗肠易激综合征、炎症性肠病和其他排便障碍。控制肠道分泌的肠神经元。