Electrophysiological Events Underlying Human Gastric Motility.

PROJECT SUMMARY The stomach is a remarkable organ that can accept and store considerable volumes of food, reduce the size of food particles to a suitable size, and efficiently empty nutrients into the duodenum. Unfortunately, functional disorders of gastric motility plague many people and effective therapies are lacking because basic mechanisms of human gastric motility are poorly understood. Much of what is known about gastric electrophysiology is derived from studies of laboratory animals, but such extrapolation may or may not accurately describe mechanisms of human gastric motor activity. The mixed genetic background of humans also makes generalization of concepts more complicated. In addition, little is known about sex differences, ethnicity or the effects of aging on gastric pacemaker mechanisms. Yet gastric motor disorders, such as gastroparesis or functional dyspepsia, are more prevalent in women and enhanced with age. In this project we will exploit a rare opportunity to systematically investigate the morphology and molecular phenotype and electrophysiology of human gastric muscles. It is possible that new weight-loss drugs (e.g. GLP-1R agonists; SGLT-2 inhibitors) will reduce the need for bariatric surgery. Thus, opportunities to study human gastric muscles may decrease in the future. Three specific aims will be pursued in this project: (i) Characterize the morphology and molecular phenotype of interstitial cells of the SIP syncytium in human gastric muscles. ii) Investigate the mechanisms responsible for pacemaker activity and slow wave propagation in the human stomach. iii) Investigate the functional role of PDGFRa+ cells and integrated regulation of gastric electrical and mechanical activity resulting from inputs of ICC and PDGFRa+ cells. Our experiments will utilize intracellular microelectrode recordings from human gastric muscles in vitro. This technique provides recordings of authentic transmembrane electrophysiology that will allow evaluation of the mechanisms responsible for electrical slow waves. Single nuclei gene expression studies (snRNA-seq) will determine additional components of the human gastric pacemakersome, and Ca2+ imaging will characterize Ca2+ handling mechanisms in ICC and SMCs. Additional studies will investigate the morphological and functional components of active propagation in gastric muscles. This project will develop a mechanistic description of electrical rhythmicity in human gastric muscles, clarify similarities and differences between gastric pacemaker activity in humans and laboratory animals, and provide novel baseline information that will be useful for physicians and the development of therapeutics for gastric motility disorders.