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。这些拟议研究要检验的总体假设是，通过 PVG 传输信息的机制在肠道炎症期间发生了改变。本申请中提出的实验将通过解决三个具体目标来检验这一假设。具体目标 1 检验了以下假设：TNBS 诱导的结肠炎会导致 IFAN 缺失，从而导致 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。具体目标 2 检验以下假设：回肠 PVG 神经元末端区域 12A 肾上腺素受体 (AR) 的表达和功能在 TNBS 或乙酸诱导的结肠炎发作后增加。具体目标 3 测试了以下假设：PVG 中的嘌呤能和谷氨酸能突触传递以及结肠炎期间 12A AR 表达的变化导致小肠运动功能改变。该提议的总体假设得到了初步数据的支持，这些数据表明结肠炎期间 PVG 神经元的生理学发生了一些明显的变化。炎症会导致 PVG 神经元的兴奋性增加以及有助于快速突触通讯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 神经元轴突末端区域自抑制 12A AR 表达增加有关。通过阻止入侵动作电位导致去甲肾上腺素释放，增强的 12A AR 会导致交感神经流出减少至更正常的水平。 PVG 神经元生理学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，所提出的实验是了解结肠炎期间 PVG 神经元功能变化的系统方法。这些实验的结果可能有助于了解调节 PVG 神经元生理学的新机制，并可能为开发针对 PVG 调节胃肠道运动的新型治疗剂提供见解。 公共卫生相关性：供给胃肠道的神经的结构和功能的变化导致肠道炎症期间常见的症状，以及在初次损伤后可能持续很长时间的症状。交感自主神经细胞将大脑和脊髓神经细胞的信号与胃肠道神经细胞的信号整合在一起，此前尚未研究其对改变肠道功能的贡献。因此，在大肠炎症或结肠炎期间将检查这些细胞的特定变化。这些研究的结果预计将有助于了解结肠炎期间神经系统控制胃肠内容物运动发生变化的新机制，并将为开发治疗肠功能障碍的新疗法提供见解。

项目成果

Neuroplasticity and dysfunction after gastrointestinal inflammation.

胃肠道炎症后的神经可塑性和功能障碍。

• 发表时间: 2014-10
• 作者: Brierley, Stuart M;Linden, David R
• 通讯作者: Linden, David R

Diabetic neuropathy: an evaluation of the use of quercetin in the cecum of rats.

糖尿病神经病变：槲皮素在大鼠盲肠中的使用评估。

• 发表时间: 2013-10-14
• 影响因子: 4.3
• 作者: Ferreira, Paulo Emilio Botura;Lopes, Cláudia Regina Pinheiro;Alves, Angela Maria Pereira;Alves, Éder Paulo Belato;Linden, David Robert;Zanoni, Jacqueline Nelisis;Buttow, Nilza Cristina
• 通讯作者: Buttow, Nilza Cristina

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。

• 发表时间: 2010
• 作者: Bertrand, Paul P;Linden, David R
• 通讯作者: Linden, David R

Enhanced excitability of guinea pig inferior mesenteric ganglion neurons during and following recovery from chemical colitis.

化学性结肠炎恢复期间和恢复后豚鼠肠系膜下神经节神经元的兴奋性增强。

• 发表时间: 2012-11-01
• 作者: Linden; David R
• 通讯作者: David R

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

化学性结肠炎恢复期间和恢复后豚鼠回肠肌间 AH 神经元的兴奋性增强。

• 发表时间: 2013-06-17
• 影响因子: 2.5
• 作者: Linden; David R
• 通讯作者: David R