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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057236-10
Application #
8097583
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
1999-10-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2011
Total Cost
$248,983
Indirect Cost
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Tache, Yvette; Larauche, Muriel; Yuan, Pu-Qing et al. (2018) Brain and Gut CRF Signaling: Biological Actions and Role in the Gastrointestinal Tract. Curr Mol Pharmacol 11:51-71
Nieves-CintrĂ³n, Madeline; Syed, Arsalan U; Buonarati, Olivia R et al. (2017) Impaired BKCa channel function in native vascular smooth muscle from humans with type 2 diabetes. Sci Rep 7:14058
Beckett, Elizabeth A H; Sanders, Kenton M; Ward, Sean M (2017) Inhibitory responses mediated by vagal nerve stimulation are diminished in stomachs of mice with reduced intramuscular interstitial cells of Cajal. Sci Rep 7:44759
Nystoriak, Matthew A; Nieves-CintrĂ³n, Madeline; Patriarchi, Tommaso et al. (2017) Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel CaV1.2 and vasoconstriction during acute hyperglycemia and diabetes. Sci Signal 10:
Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe. J Physiol 594:1515
Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) CrossTalk proposal: Interstitial cells are involved and physiologically important in neuromuscular transmission in the gut. J Physiol 594:1507-9
Sanders, Kenton M; Kito, Yoshihiko; Hwang, Sung Jin et al. (2016) Regulation of Gastrointestinal Smooth Muscle Function by Interstitial Cells. Physiology (Bethesda) 31:316-26
Baker, Salah A; Drumm, Bernard T; Saur, Dieter et al. (2016) Spontaneous Ca(2+) transients in interstitial cells of Cajal located within the deep muscular plexus of the murine small intestine. J Physiol 594:3317-38
Hwang, Sung Jin; Basma, Naseer; Sanders, Kenton M et al. (2016) Effects of new-generation inhibitors of the calcium-activated chloride channel anoctamin 1 on slow waves in the gastrointestinal tract. Br J Pharmacol 173:1339-49
Yang, Shao H; Procaccia, Shiri; Jung, Hea-Jin et al. (2015) Mice that express farnesylated versions of prelamin A in neurons develop achalasia. Hum Mol Genet 24:2826-40

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