Regulatory mechanisms in intestinal motility

肠道蠕动的调节机制

• 批准号: 9067268
• 负责人: KENTON M SANDERS
• 金额: $ 156.06万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067268
• 关键词: Achalasia; Action Potentials; Affect; Agonist; Animal Model; Behavior; Biological Markers; Cell Separation; Cells; Colitis; Collaborations; Colon; Constipation; Coupling; Data; Development; Disease; Distal; Elements; Employee Strikes; Enteral; Fluorescence-Activated Cell Sorting; Funding; Gastrointestinal Motility; Gastrointestinal tract structure; Gastroparesis; Gene Expression Profiling; Gene Proteins; Generations; Genes; Giant Cells; Growth; Health; Human; Indium; Inflammatory; Informatics; Interstitial Cell of Cajal; Intestinal Motility; Intestines; Investigation; Knock-out; Knowledge; Laboratories; Link; Maps; Mediating; Mesenchymal; Metabolic; Metabolic Pathway; Methods; Microfluidics; Modeling; Molecular; Monkeys; Motor; Motor Neurons; Movement; Mus; Muscle; Muscle Cells; Natural regeneration; Neuromodulator; Neurotransmitters; Nutrient; Obstruction; Organ; Organ Culture Techniques; Pacemakers; Participant; Pathway interactions; Patients; Pattern; Periodicity; Phase; Phenotype; Physiological; Play; Population; Process; Productivity; Program Research Project Grants; Purines; RNA Splicing; Recovery; Reflex action; Regulation; Regulatory Pathway; Research; Research Personnel; Response to stimulus physiology; Rodent; Role; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Stimulus; Techniques; Technology; Testing; Tissues; Transcript; Transgenic Animals; Transgenic Mice; Transplantation; Variant; Work; base; cell motility; data management; deep sequencing; design; gastrointestinal; innovation; interest; molecular phenotype; motility disorder; motor disorder; neuroregulation; neurotransmission; nodal myocyte; nonhuman primate; novel; novel strategies; programs; public health relevance; receptor; relating to nervous system; research study; response; transcriptome; ward; wasting

DESCRIPTION (provided by applicant): This Program Project grant is designed to enhance our understanding of the basic mechanisms responsible for gastrointestinal (Gl) motility. Knowledge of mechanisms that generate normal motility patterns will help explain what goes awry in motility disorders and develop novel approaches to therapies. In this Program we are investigating smooth muscle cells, Interstitial cells of Cajal (ICC) and PDGFRa+ cells of Gl muscles, which through electrical coupling, form a syncytial tissue we refer to as the SIP syncytium. Cells of the SIP syncytium generate electrical pacemaker activity and provide what has been known as 'myogenic' regulation of motility. SIP cells also receive and transduce inputs from enteric motor neurons, so they are key participants in neural regulation of motility. We have developed techniques to isolate and purify each class of cell in the SIP syncytium, and we have performed deep sequencing of the gene transcripts in these cells. Hypotheses in this proposal were developed from this unprecedented knowledge of the cell-specific transcriptomes of SIP cells. Four projects will investigate questions regarding the mechanism of pacemaking and propagation of electrical slow waves, integration of excitatory responses by ICC and smooth muscle cells in generation of propulsive colonic contractions, bioactivity and targets of purines released and metabolites produced in colonic muscles, and the fate and recovery of ICC in patho-physiological conditions causing loss of ICC. Three Core laboratories will support these projects. Core A will provide informatics support and aide investigators with experimental planning and data management. Core B will provide transgenic animal, isolate and sort cells by fluorescence activated cell sorting, and support organ cultures. Core C will analyze expression of genes and proteins in cells and tissues. Experiments will utilize transgenic mice as model organisms to test novel hypotheses. Ideas developed in rodent studies will be tested on cells and muscles of non-human primates and human patients. The research team is highly synergistic and collaborative and has a long track record of productivity and innovative contributions to neurogastroenterology.

描述（由申请人提供）：该计划项目拨款旨在增强我们对胃肠道 (GI) 运动的基本机制的理解。了解产生正常运动模式的机制将有助于解释运动障碍的原因并开发新的治疗方法。在这个项目中，我们正在研究平滑肌细胞、Cajal 间质细胞 (ICC) 和胃肠道肌肉的 PDGFRa+ 细胞，它们通过电耦合形成合胞组织，我们称之为 SIP 合胞体。 SIP 合胞体细胞产生电起搏器活性并提供所谓的“肌源性”运动调节​​。 SIP 细胞还接收和转导来自肠运动神经元的输入，因此它们是运动性神经调节的关键参与者。我们开发了分离和纯化 SIP 合胞体中各类细胞的技术，并对这些细胞中的基因转录本进行了深度测序。该提案中的假设是根据对 SIP 细胞的细胞特异性转录组的前所未有的了解而提出的。四个项目将研究以下问题：电慢波的起搏和传播机制、ICC 和平滑肌细胞在产生推进性结肠收缩时的兴奋性反应的整合、结肠肌肉中释放的嘌呤和代谢物的生物活性和目标以及命运以及导致 ICC 丧失的病理生理条件下 ICC 的恢复。三个核心实验室将支持这些项目。核心 A 将提供信息学支持并协助研究人员进行实验规划和数据管理。 Core B将提供转基因动物，通过荧光激活细胞分选来分离和分选细胞，并支持器官培养。 Core C 将分析细胞和组织中基因和蛋白质的表达。实验将利用转基因小鼠作为模型生物来测试新的假设。啮齿动物研究中提出的想法将在非人类灵长类动物和人类患者的细胞和肌肉上进行测试。该研究团队具有高度的协同性和协作性，在神经胃肠病学方面有着长期的生产力和创新贡献记录。