A Mathematical Model of the Effects of Anoctamin-1 Loss on Intestinal Slow Wave Entrainment

Abstract

The interstitial cells of Cajal (ICC) generate electrophysiological events called slow waves that regulate the motility of the gastrointestinal (GI) tract. Recent studies have demonstrated that the Ca2+-activated Cl- -channel, encoded by the anoctamin1 (Ano1) protein, has a major role in regulating intestinal slow waves and motility. The main aim of this study was to develop a multi-scale mathematical model capable of simulating both normal slow wave entrainment and the effects of Ano1 knockout (KO) on the normal activity. A biophysically-based cell model was adapted to simulate the effects of Ano1 KO at the cellular level. A 10mm one-dimensional (1D) model was then developed to simulate entrained intestinal slow wave propagation. Cellular KO at levels of 100% and 20% were applied to a varying-sized middle region of the 1D model. The main finding was that the level of loss of entrainment increased as both cellular and spatial Ano1 KO levels increased, mostly manifesting as ectopic activation. In the future, this model will be extended and used in combination with Ca2+ -imaging data to quantitatively investigate the effects of Ano1 loss in ICC.