Extrinsic Neural Control of Gastrointestinal Function in the Disordered Bowel

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）提供持续的交感张力。此外，这些神经元通过位于肠壁的肠传入神经元（IFANs）发起的反射来协调运动、分泌和血管功能。这些拟议的研究要验证的总体假设是，在肠道炎症期间，信息通过PVG传递的机制发生了改变。本应用程序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Aim 1验证了tnbs诱导的结肠炎导致IFANs缺失的假设，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。特异性目的2验证了在TNBS或醋酸性结肠炎发生后，回肠PVG神经元末端野12A肾上腺素能受体（ARs）的表达和功能增加的假设。特异性目的3验证了PVG中嘌呤能和谷氨酸能突触传递以及结肠炎期间12A ar表达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神经元的几个明显的生理变化支持了这一提议的总体假设。炎症引起PVG神经元的兴奋性增加，并改变有助于快速突触通信的嗜离子受体。这可能会增加交感神经向胃肠道的流出。此外，结肠炎与PVG神经元轴突末端区自身抑制性12A ARs的表达增加有关。通过阻止入侵的动作电位引起去甲肾上腺素的释放，增强的12A 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促进机制。总的来说，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，并可能为开发针对PVG调节GI运动的新型治疗药物提供见解。

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.