INTERSTITIAL CELL OF CAJAL IN VAGAL AFFERENT SENSITIVITY

胃底的平滑肌层产生紧张性收缩或松弛，在胃容量的调节中起关键作用。进食后，近端胃放松，以适应胃容量的增加，而不会同时改变胃压力。这种适应被称为适应性松弛，既受内在神经控制，也受外在神经控制。位于肌层的迷走神经传入牵张敏感纤维受到胃扩张的刺激，触发迷走神经传出和局部肠道通路，从而增加胃动力和胃排空。数以百万计的功能性消化不良和胃轻瘫患者，包括特发性和与糖尿病相关的患者，迷走神经张力降低，餐后胃餐调节受损，经常伴随腹痛、腹胀和恶心的症状。采用形态学和生理学相结合的方法，本研究的长期目标是确定迷走神经和肠道传入敏感机制中发生的变化，这些变化与缺乏Cajal间质细胞(ICC)的动物的胃适应能力的显著变化有关。为了解决这一主要目标，本项目的具体目标将研究Cajal间质细胞(ICC)的重要性，ICC在胃的肌层中被发现为肌肉内阵列：i)胃中迷走神经传入纤维的发育、引导和维持。2)ICC是否具有串联牵张敏感通道，可触发传入通路和胃调节。Iii)确定ICC在胃调节中的作用，以及ICC缺失是否会影响ICC缺失突变小鼠的迷走神经传入放电和胃调节。这些研究工作将与结构研究相结合，以确定成年动物和发育中的动物迷走神经传入阵列和肌肉内ICC之间的形态关系。这项提案中概述的实验将提供有关ICC在胃中传入拉伸敏感性中所起作用的重要的新信息。这一信息也可以扩展到胃肠道的其他器官。通过这样做，我们将有助于未来的研究，以了解这些细胞如何在病理生理疾病状态中发挥关键作用。

The smooth muscle layers of the gastric fundus generate tonic contraction or relaxation and are critical in the regulation of gastric volume. Upon food ingestion the proximal stomach relaxes to accommodate the increases in gastric volume without concurrent changes in gastric pressure. This accommodation, known as adaptive relaxation, is under both intrinsic and extrinsic neural control. Vagal afferent stretch sensitive fibers located in the muscle layers are stimulated by gastric distension and trigger vagovagal efferent and local enteric pathways that increase gastric motility and gastric emptying. Millions of patients with functional dyspepsia and gastroparesis, both idiopathic and that associated with diabetes mellitus, have low vagal tone and impaired postprandial gastric meal accommodation which is often accompanied with symptoms of abdominal pain, bloating and nausea. Using a combined morphological and physiological approach, the broad long term objective of the present study is to determine the changes which occur in vagal and enteric afferent sensitive mechanisms that are associated with dramatic changes in gastric accommodation in animals lacking interstitial cells of Cajal (ICC). To address this main objective, the specific aims of this project will examine the importance of interstitial cells of Cajal (ICC), which are found as intramuscular arrays in the muscle layers of the stomach in: I) The development, guidance and maintenance of vagal afferent fibers in the stomach. ii) Whether ICC possess in-series stretch sensitive channels that could trigger afferent pathways and stomach accommodation. iii) To determine the role of ICC in gastric accommodation and whether loss of ICC affects vagal afferent discharge and gastric accommodation in mutant mice lacking ICC. These studies work will be combined with structural studies to determine the morphological relationships between vagal afferent arrays and intramuscular ICC in adult and developing animals. Experiments outlined in this proposal will provide important novel information on the role of ICC in afferent stretch sensitivity in the stomach. This information could also be extended to other organs of the gastrointestinal tract. In doing so we will aid future studies toward understanding how these cells may be critical in pathophysiological disease states.