Millions of patients with functional dyspepsia and gastroparesis, both idiopathic and that associated with diabetes mellitus, have impaired postprandial gastric meal accommodation and uncoordinated gastric contractions which are often accompanied with symptoms of abdominal pain, bloating and nausea. Our hypothesis is that many of these gastric disorders are produced by a disruption in interstitial cells of Cajal (ICC) that are critical for: (i) neurally mediated contractions and relaxations and (ii) rhythmic depolarizations that lead to the electrical and mechanical activities observed in the phasic regions of the stomach. Upon food ingestion the proximal stomach relaxes to accommodate increases in gastric volume without concurrent changes in gastric pressure. The distal stomach responds to gastric distension by increasing phasic motor activity that aids in the breakdown and digestion of gastric contents. The objectives of this proposal are to determine the differences in specific populations of intramuscular ICC (ICC-IM) in the fundus, corpus and antrum and how these differences contribute to the regional diversity in the way the stomach responds to distension following ingestion of a meal. A reductionism approach will be undertaken to compare differences in stretch dependent responses in tissues, isolated muscle bundles and freshly dispersed ICC-IM and smooth muscle cells from three regionally distinct areas of the stomach. The functional roles of ICC- IM will be resolved by examining tissues isolated from animal models that lack ICC-IM in each of these regions and have delayed gastric emptying, similar to that observed in gastroparetic patients. Experiments outlined in this proposal will provide important, novel information on the role of ICC-IM in gastric motor actviity and how differences in the expression of ionic conductances in ICC-IM result in regional diversity in gastric motor activity. The information presented in this proposal is critical towards understanding how specific populations of ICC are involved in gastric accomodation or increased pacemaking activity in the stomach wall following meal ingestion and how the loss of these specalized cells could contribute to lead to impaired gastric accomodation and gastric motor dysfunction in patients suffering from dyspepsia or gastroparesis. ? ? ?
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