PURINERGIC NEUROGENIC MUCOSAL SECRETION

嘌呤能神经源性粘膜分泌

基本信息

批准号：
7257147
负责人：
JACKIE D WOOD
金额：
$ 28.35万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7257147
关键词：
ATP Receptors Abdominal Pain Address Agonist Amino Acids Bathing Binding Calcium-Binding Proteins Cavia Cell Line Cells Chemical Stimulation Chemicals Chromosome Pairing Code Coupling Data Defecation Development Disease Electric Stimulation Electrodes Electrophysiology (science)Enteral Enteric Nervous System Excitatory Postsynaptic Potentials Fiber GTP-Binding Proteins Ganglia Genes Human In Situ Hybridization Inflammatory Bowel Diseases Intestinal Secretions Intestines Ion Channel Irritable Bowel Syndrome Label Lead Localized MRS2179 Mammalian Cell Measurement Mediating Mesentery Messenger RNA Metabolic Metabolic Pathway Methods Molecular Molecular Cloning Myenteric Plexus Myxoid cyst Nerve Neuroepithelial Neurons Neuropharmacology Neurotransmitters Northern Blotting Organ Pathway interactions Peptides Pertussis Toxin Pharmaceutical Preparations Pharmacology Phospholipase C Pilot Projects Point Mutation Preparation Reflex action Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Role Serotonin Signal Pathway Source Submucous Plexus Suggestion Synapses Synaptic Potentials System Testing Transcript Wood material Work Xenopus oocyte ileum neurotransmitter release novel programs purinoceptor P2Y1 receptor receptor expression release of sequestered calcium ion into cytoplasm research study response synthetic enzyme voltage clamp

项目摘要

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）：该项目的总体目的是表征一种新型的嘌呤能缓慢兴奋性突触后潜能（EPSP），该爆发是由肠神经系统中代谢性ATP受体（P2Y1受体）介导的。嘌呤能存在的证据减慢了EPSP，而P2Y1受体拮抗剂MRS2179选择性地阻断了慢速EPSP和慢速EPSP样反应，而ATP在亚核神经元中诱发了慢速EPSP和慢速EPSP样反应。嘌呤能缓慢的EPSP是通过在粘膜下泌尿蛋白神经元中ATP和P2Y1受体突触释放介导的，将在形态学上鉴定的神经元中进行药理测试。分子克隆和功能表达将用于更好地表征P2Y1受体。该提议来自试验/可行性结果，这表明肠道秘密神经元从肌室神经元中获得肠道秘密促进神经元的嘌呤能缓慢的兴奋性突触输入，来自肌肉神经元的邻近神经元，来自亚us骨神经元的邻近神经元，以及来自prevertebral Ganglia中的交感神经元。对该假设的更多支持来自于发现，选择性P2Y1受体拮抗剂MRS2179抑制了通过ATP的应用和在USSSING室内实验中的秘密运动神经元的透射电动神经元所引起的神经源性分泌反应。满足该提案的目标将使人们更好地理解新发现的嘌呤能慢性EPSP在肠神经系统中在细胞，分子和整合系统水平上的作用。试验/可行性数据是第一个证明肠神经系统中功能性嘌呤能缓慢EPSP的数据。 P2Y1受体在肠道秘密运动神经元中介导缓慢的EPSP的发现可能有助于开发新药，以治疗肠易激综合征，炎症性肠病和其他排便疾病，通过靶向P2Y1受体或ATP ATP代谢途径的其他疾病控制肠道分泌的肠神经元。