Extrinsic Neural Control of Gastrointestinal Function in the Disordered Bowel

描述(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分离肠传入神经元(IFANS)启动的反射来协调运动、分泌和血管功能。这些拟议的研究将检验的总体假设是，通过PVG传递信息的机制在肠道炎症过程中发生了变化。本申请中提出的实验将通过解决三个具体目标来验证这一假设。特异性目的1验证TNBS诱导的结肠炎导致PVG神经元功能嘌呤能和谷氨酸能配基门控离子通道表达增加的假说。特异性目的2验证了回肠PVG神经元终末野上12A肾上腺素能受体(ARs)的表达和功能在TNBS或乙酸性结肠炎发病后增加的假说。特异性目标3验证了下丘脑室旁核中的嘌呤能和谷氨酸能突触传递以及结肠炎期间12A受体表达的变化导致小肠运动功能改变的假说。初步数据表明，在结肠炎期间PVG神经元的生理发生了几个明显的变化，这一假设得到了初步数据的支持。炎症导致PVG神经元兴奋性增加，并改变有助于快速突触通讯的离子亲和性受体。这可能有助于增加胃肠道的交感神经流出。此外，结肠炎与PVG神经元轴突终末区域自抑制性12A受体的表达增加有关。通过阻止侵袭性动作电位引起去甲肾上腺素的释放，增强的12AARs将导致交感神经流出减少到更正常的水平。PVG神经元的这些生理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的肠功能障碍的潜在贡献机制。总体而言，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提供对PVG神经元生理调节的新机制的理解，并可能为开发以PVG为靶点来调节胃肠运动的新型治疗剂提供洞察力。 与公共卫生相关：供应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，以及在最初的侮辱后可能持续很长时间的症状。交感自主神经细胞将来自大脑和脊髓神经细胞的信号与来自胃肠道神经细胞的信号整合在一起，以前还没有研究过它们对肠道功能改变的作用；因此，在大肠炎症或结肠炎期间，将检查这些细胞的具体变化。这些研究的结果有望提供对结肠炎期间神经系统控制胃肠内容物运动的新机制的理解，并将为开发治疗肠功能障碍的新疗法提供洞察力。

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.