The stomach is a miraculous organ that can accept large volumes of food and then grind up solids to make nutrients absorbable in the small intestine. Unfortunately some patients find eating, a palpable joy of living, an uncomfortable or painful experience. Functional disorders of gastric motility plague the lives of these patients and therapies are out of reach because the basic mechanisms of gastric motility are unknown. New techniques allow monitoring of the pacemaker activity that fuels gastric peristalsis and gastric emptying, and this project proposes to utilize cutting-edge approaches to better understand basic mechanisms of gastric motility.
Three specific aims will be pursued: i) Characterize the relationship between Ca2+ signaling patterns and pacemaker activity in interstitial cells of Cajal (ICC-MY and ICC-IM) of the mouse and human gastric corpus and antrum; ii) Compare molecular and functional characteristics of the pacemakersomes in mouse and human corpus and aims will investigate the basic cellular behaviors that generate pacemaker activity ICC-MY and ICC-IM using optogenetic and electrophysiological techniques to monitor pacemaker activity of ICC in situ. Preliminary data suggest that Ca2+ transients underlie the electrical responses known as slow waves that power gastric peristalsis. The basis for the corpus-to-antrum frequency gradient will be explored and concepts about why corpus frequency exceeds antral frequency will be investigated. The basis for propagation of slow waves in ICC networks will be investigated and the mechanisms responsible for integrated organization of pacemaker activity will be determined. Optogenetics provides the opportunity to study the pattern of ICC activation in intact gastric muscles and the intact stomach. Preliminary data reveals a novel pattern of slow wave activation never previously observed with extracellular electrical recording. We will also investigate how enteric motor neural inputs and other chronotropic mediators regulate gastric slow waves and how application of chronotropic stimuli affects the pattern of slow wave propagation in the stomach. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020)Page Continuation Format Page
Functional disorders of the proximal GI tract continue to plague many patients. Relieve from these problems depends upon a better understanding of the mechanisms of gastric motor function. Interstitial cells of Cajal (ICC) provide important regulation of gastric motility, including pacemaker activity, propagation of electrical slow waves, responses to neural regulation and coordination of gastric peristalsis required for normal gastric emptying. This project will use cutting-edge electrical and optical techniques to understand the mechanisms of pacemaker activity and neural responses in ICC networks. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020)Page Continuation Format Page
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