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

基本信息

批准号：
8033223
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
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8033223
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

项目摘要

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）：位于前脊椎神经节中（PVG）中的Ganglionic交感神经元为整个胃肠道（GI）区提供了持续的交感神经。此外，这些神经元通过位于肠壁上的肠道传入神经元（Ifans）引发的反射来协调运动，分泌和血管功能。这些提出的研究要检验的总体假设是，在肠道炎症期间，通过PVG传播信息的机制。本应用程序中提出的实验将通过解决三个特定目标来检验该假设。具体目标1检验了TNBS诱导的结肠炎的假设会导致IFAN损失，从而导致PVG神经元中功能性嘌呤能和谷氨酸能配方的离子通道的表达增加。具体目标2检验了以下假设：在TNBS或乙酸诱导的结肠炎开始后，在回肠中PVG神经元末端的12A肾上能受体（ARS）的表达和功能增加。具体目标3检验了以下假设：珀诺能和谷氨酸能在PVG中的突触传播以及结肠炎过程中12A ARS表达的变化导致小肠运动功能改变。该提案的总体假设得到了初步数据的支持，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。炎症会导致PVG神经元的兴奋性增加，以及导致快速突触通信的离子受体的变化。这可能有助于增加对胃肠道的交感神经流出。此外，结肠炎与PVG神经元的轴突末端场上自身抑制12A ARS的表达增加有关。通过阻碍入侵的动作电位引起去甲肾上腺素的释放，增强的12A ARS将导致交感神经外流降低到更正常的水平。 PVG神经元生理学变化与回肠运动功能改变的这些变化之间的时间关系将阐明潜在的促进临床相关肠功能障碍的机制。总的来说，提出的实验是一种系统的方法，可以理解结肠炎期间PVG神经元功能的变化。这些实验的结果可能会提供对PVG神经元生理学的新机制的理解，并可能为靶向PVG的新型治疗剂的发展提供洞察力，以调节GI运动。公共卫生相关性：供应胃肠道的神经结构和功能的变化会导致肠道炎症期间通常遇到的这两种症状，以及在最初侮辱很久以后可能会持续存在的症状。以前没有研究过交感的自主神经细胞，这些神经细胞将大脑中神经细胞的信号与胃肠道中神经细胞的信号与胃肠道的信号整合在一起，以前尚未被研究过，因为它们对改变肠道功能的改变了。因此，将在大肠或结肠炎的炎症期间检查这些细胞的特定变化。预计这些研究的结果将提供对新机制的理解，通过这种机制，神经系统对胃肠道含量运动的控制在结肠炎期间会改变，并将为肠功能障碍治疗的新疗法提供洞察力。