Dissertation

A Quantitative Model of the Sip Syncytium

Yier, Li

2020

Overview

The “SIP” syncytium is a multicellular system in which smooth muscle cells (“S”), interstitial cells of Cajal (“I”), and platelet-derived growth factor receptor alpha-positive cells (“P”) are coupled via gap junctions. This electrical coupling allows changes in electrical conductance of cell type to modulate the excitability of other cell types in the syncytium. Gastrointestinal (GI) motility is further regulated by inputs from the enteric nervous system (ENS) through both excitatory and inhibitory enteric motor neurons. The basal excitability of the GI musculature is believed to be the result of a balance between the excitatory and inhibitory influences exerted by the interstitial cells. A disruption to this balance, caused by dysfunction of interstitial cells, could explain some of the symptoms observed in motility disorders. A lack of understanding of the mechanisms underlying GI disorders such as constipation, irritable bowel syndrome (IBS), idiopathic gastroparesis, and functional dyspepsia has hindered the effectiveness of clinical diagnosis and therapy. Computational models can succinctly describe complex biological systems with input from experimental data and help in developing a better understanding of the underlying physiological and pathophysiological processes.In this work, we aim to describe electrical activity in the SIP syncytium and its potential correlation to motility disorders. First, we constructed a phenomenological model to describe the Ca2+ transients in platelet-derived growth factor receptor alpha-positive (PDGFRα +) cells and investigated effect of Ca2+ transients on tonic inhibition in the GI musculature through tissue simulations. Second, we constructed a biophysically-based intramuscular interstitial cell of Cajal (ICC-IM) model with descriptions of the major ion channels, receptors, and intracellular process necessary to describe their role in mediating cholinergic neurotransmission. We have adapted our Ca2+ transient model to study the depolarising influence of Ca2+ transients in ICCIM on the GI musculature. Finally, we have integrated the excitatory and inhibitory effects exerted by both types of interstitial cells on the GI smooth muscle by developing a modelling framework which is capable of describing the electrophysiology of tissues with three cell types.From the in silico experiments, we demonstrate that the basal electrical activity observed in the GI smooth muscle tissue may be the result of a balance between excitatory and inhibitory influences within the SIP syncytium. We also demonstrate that disabling various inhibitory components within the SIP syncytium could produce an analogue similar to the symptoms of diarrhoea predominant IBS.The models developed in this work have been validated against experimental recordings. These models provide a basis for a better understanding of the underlying pathophysiology of GI motility disorders.

• Publisher: ProQuest Dissertations & Theses
• Subject: Adenosine triphosphate / Anatomy & physiology / Cancer / Cells / Cellular biology / Chloride / Colon / Constipation / Drug therapy / Endoplasmic reticulum / Growth factors / Irritable bowel syndrome / Large intestine / Morphology / Motility / Muscle contraction / Nervous system / Neurosciences / Pacemakers / Physiology / Polypeptides / Potassium / Smooth muscle / Therapy
• ISBN: 9798374484953