INTERSTITIAL CELL OF CAJAL IN VAGAL AFFERENT SENSITIVITY

胃底的平滑肌层产生紧张性收缩或舒张，并且在胃容量的调节中是关键的。 在食物摄入后，近端胃松弛以适应胃体积的增加，而不同时改变胃压力。 这种调节，被称为适应性放松，是在内在和外在神经控制下。 位于肌肉层中的迷走神经传入牵张敏感纤维受到胃扩张的刺激，并触发迷走神经传出和局部肠通路，从而增加胃运动和胃排空。 数以百万计的功能性消化不良和胃轻瘫患者，无论是特发性的还是与糖尿病相关的，都具有低迷走神经张力和餐后胃适应性受损，这通常伴有腹痛、腹胀和恶心的症状。本研究采用形态学和生理学相结合的方法，旨在确定迷走神经和肠道传入敏感机制的变化，这些变化与缺乏Cajal间质细胞（ICC）的动物胃调节的显著变化有关。 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，这些细胞在胃的肌肉层中被发现为肌内阵列：I）胃中迷走神经传入纤维的发育，指导和维持。ii）ICC是否具有串联的牵张敏感通道，可以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，以确定迷走神经传入阵列和成年和发育中的动物肌内ICC之间的形态学关系。 在这个建议中概述的实验将提供重要的新信息ICC在传入拉伸敏感性在胃中的作用。 这一信息也可以扩展到胃肠道的其他器官。 在这样做的过程中，我们将帮助未来的研究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.