Extrinsic Neural Control of Gastrointestinal Function in the Disordered Bowel

肠道紊乱胃肠功能的外在神经控制

• 批准号: 8217087
• 负责人: David R. Linden
• 金额: $ 29.62万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217087
• 关键词: Acetic Acids; Acetylcholine; Action Potentials; Address; Adrenergic Receptor; Afferent Neurons; Afferent Pathways; Animal Model; Binding Sites; Blood Vessels; Boxing; Brain; Catheters; Cavia; Cells; Charcoal; Colitis; Colon; Communication; Data; Development; Disease; Distal; Event; Functional disorder; Ganglia; Gastrointestinal Contents; Gastrointestinal Motility; Gastrointestinal tract structure; Gated Ion Channel; Glutamate Receptor; Glutamates; Gray unit of radiation dose; Implant; In Vitro; Inflammation; Inflammatory; Inflammatory disease of the intestine; Intestines; Invaded; Label; Large Intestine; Ligands; Modeling; Motor; Movement; Myenteric Plexus; N-Methylaspartate; Nerve; Nervous system structure; Neurons; Norepinephrine; P2X-receptor; Patients; Physiological; Physiology; Presynaptic Terminals; Purines; Purinoceptor; Recovery; Reflex action; Rest; Signal Transduction; Small Intestines; Solutions; Spinal Cord; Structure; Sympathectomy; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic Agents; Time; Ulcerative Colitis; Vascular blood supply; autonomic nerve; clinically relevant; design; gastrointestinal function; ileum; insight; mRNA Expression; nerve supply; neuroregulation; novel; novel therapeutics; prevent; public health relevance; purine; receptor; receptor binding; receptor expression; relating to nervous system; research study; restoration

DESCRIPTION (provided by applicant): Postganglionic sympathetic neurons located in the prevertebral ganglia (PVG) provide ongoing sympathetic tone to the entire gastrointestinal (GI) tract. In addition, these neurons coordinate motor, secretory and vascular functions via reflexes initiated by intestinofugal afferent neurons (IFANs) located in the wall of the intestine. The overall hypothesis to be tested by these proposed studies is that the mechanisms by which information is transmitted through the PVG are altered during intestinal inflammation. Experiments proposed in this application will test this hypothesis by addressing three specific aims. Specific Aim 1 tests the hypothesis that TNBS-induced colitis causes a loss of IFANs that result in the increased expression of functional purinergic and glutamatergic ligand-gated ion channels in PVG neurons. Specific Aim 2 tests the hypothesis that the expression and function of 12A adrenergic receptors (ARs) on the terminal fields of PVG neurons in the ileum is increased following the onset of TNBS or acetic acid induced colitis. Specific Aim 3 tests the hypothesis that purinergic and glutamatergic synaptic transmission in the PVG and a change in the expression of 12A ARs during colitis result in altered motor function in the small intestine. The overall hypothesis of this proposal is supported by preliminary data indicating several distinct changes in the physiology of PVG neurons during colitis. Inflammation causes an increased excitability of PVG neurons and a change in the ionotropic receptors that contribute to fast synaptic communication. This would likely contribute to increased sympathetic outflow to the GI tract. In addition, colitis is associated with an increased expression of autoinhibitory 12A ARs on the axon terminal fields of PVG neurons. By impeding invading action potentials from causing norepinephrine release, enhanced 12A ARs would result in a reduction of sympathetic outflow to more normal levels. The temporal relationship between these changes in the physiology of PVG neurons and altered ileal motor function will elucidate potential contributing mechanisms to clinically relevant bowel dysfunction. Collectively, the experiments proposed are a systematic approach to understanding the change in function of PVG neurons during colitis. The results of these experiments are likely to provide an understanding of new mechanisms by which the physiology of PVG neurons is regulated and may provide insight to the development of novel therapeutic agents that target the PVG to regulate GI motility. Public Health Relevance: Changes in the structure and function of the nerves that supply the gastrointestinal tract contribute to both symptoms commonly encountered during intestinal inflammation, as well as symptoms that can persist long after the initial insult. Sympathetic autonomic nerve cells, which integrate signals from nerve cells in the brain and spinal cord with signals from nerve cells in the gastrointestinal tract, have not previously been studied for their contribution to altered gut function; therefore specific changes in these cells will be examined during inflammation of the large intestine, or colitis. The results of these studies are expected to provide an understanding of new mechanisms by which the nervous system control of movements of gastrointestinal contents is altered during colitis and will provide insight to the development of new therapies for the treatment of bowel dysfunction.

描述（由申请人提供）：位于椎前神经节（PVG）的节后交感神经元为整个胃肠道（GI）提供持续的交感神经张力。此外，这些神经元通过位于肠壁中的离肠传入神经元（IFAN）发起的反射来协调运动、分泌和血管功能。这些拟议的研究所要检验的总体假设是，在肠道炎症期间，通过PVG传递信息的机制发生了改变。本申请中提出的实验将通过解决三个具体目标来测试这一假设。具体目的1检验TNBS诱导的结肠炎引起IFAN损失的假设，IFAN损失导致PVG神经元中功能性嘌呤能和谷氨酸能配体门控离子通道的表达增加。具体目的2检验了以下假设：在TNBS或乙酸诱导的结肠炎发作后，回肠中PVG神经元的终末区域上的12 A肾上腺素能受体（AR）的表达和功能增加。具体目标3测试PVG中的嘌呤能和多巴胺能突触传递以及结肠炎期间12 A AR表达的变化导致小肠运动功能改变的假设。初步数据表明，结肠炎期间PVG神经元的生理学发生了几种不同的变化，这一提议的总体假设得到了支持。炎症引起PVG神经元的兴奋性增加和有助于快速突触通信的离子型受体的变化。这可能会导致胃肠道交感神经流出增加。此外，结肠炎与PVG神经元轴突终末野上自身抑制性12 A AR的表达增加相关。通过阻止侵入动作电位引起去甲肾上腺素释放，增强的12 A AR将导致交感神经流出减少到更正常的水平。PVG神经元生理学的这些变化与回肠运动功能改变之间的时间关系将阐明临床相关肠功能障碍的潜在机制。总的来说，提出的实验是一个系统的方法来了解结肠炎期间PVG神经元的功能变化。这些实验的结果可能提供一个新的机制，PVG神经元的生理调节的理解，并可能提供洞察力的新的治疗药物的发展，目标PVG调节胃肠道运动。 公共卫生相关性：供应胃肠道的神经的结构和功能的变化有助于肠道炎症期间常见的症状，以及在初始损伤后长期存在的症状。交感自主神经细胞整合来自大脑和脊髓中的神经细胞的信号与来自胃肠道中的神经细胞的信号，以前没有研究过它们对肠道功能改变的贡献;因此，在大肠或结肠炎炎症期间将检查这些细胞的特定变化。这些研究的结果预计将提供一个新的机制，其中神经系统控制的运动，胃肠道内容物在结肠炎期间改变的理解，并将提供洞察力的新疗法的发展，用于治疗肠功能障碍。

项目成果

Enhanced excitability of guinea pig ileum myenteric AH neurons during and following recovery from chemical colitis.

• DOI: 10.1016/j.neulet.2013.04.021
• 发表时间: 2013-06-17
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Linden DR

Getting a handle on cholera and the circuits controlling intestinal motility.

控制霍乱和控制肠道蠕动的回路。

• DOI: 10.3389/fnins.2010.00197
• 发表时间: 2010
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Bertrand,PaulP;Linden,DavidR
• 通讯作者: Linden,DavidR