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.
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