Functional and Dysrhythmic Slow Waves in the Stomach - An In Silico Study

Authors

Md Ashfaq Ahmed, Florida International UniversityFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Engineering

First Advisor's Name

Dr. Ranu Jung

First Advisor's Committee Title

Committee Chair

Second Advisor's Name

Dr. James Abbas

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Dr. Lidia Kos

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Dr. Jacob McPherson

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Dr. Jessica Ramella Roman

Fifth Advisor's Committee Title

Committee member

Sixth Advisor's Name

Dr. Sharmila Venugopal

Sixth Advisor's Committee Title

Committee member

Keywords

Slow-wave, gastric motility, entrainment, coupled oscillators, gap junction, IP3, gap junction blocker, endogenous neurotransmitter, Acetylcholine

Date of Defense

6-29-2021

Abstract

Peristalsis, the coordinated contraction and relaxation of the muscles of the stomach, is important for normal gastric motility and is impaired in motility disorders. Coordinated electrical depolarizations that originate and propagate within a mutually coupled network of interstitial cells of Cajal (ICC) and smooth muscle cells of the stomach wall as a slow-wave, underly peristalsis. Normally, the gastric slow-wave (GSW) oscillates with a single period and uniform rostro-caudal lag, exhibiting network entrainment. Loss of entrainment in the coupled network and the resulting impairment in slow-wave propagation is associated with various gastric motility disorders. Our study provides an enhanced understanding of physiological mechanisms that may underlie gastric motility disorders. This understanding may benefit in the design of new drugs and treatment therapies targeted to specific cellular pathways as well as improvements in current therapies such as gastric pacemaking neurotechnology.

We hypothesize that engaging biological oscillators (ICCs) through second messenger pathways permits robust entrainment essential for gastric peristalsis, which can be disrupted by gap junction deficiency or elevated neurotransmitter release. Using a computational framework, we show that stronger electrical coupling and exchange of second messengers (in particular, inositol trisphosphate (IP₃)) are complementary mechanisms and increase the range of the entrained network. We also show that the distinct intercellular coupling in conjunction with the intracellular feedback pathways and a rostro-caudal neural stimulus gradient allows the gastric slow-wave to oscillate within a moderate range of frequencies and to propagate with a broad range of velocities, thus preventing decoupling observed in motility disorders. We find that aberrant responses of different parts of the stomach (corpus, antrum etc.) to exogenous application of excitatory neurotransmitters such as Acetylcholine, can be explained by an interplay between the level of neurotransmitter and density of receptors available while blockade of gap junctions (which mimics gap junction deficiency) results in retrograde propagation of the slow-wave.

To address our hypotheses, a physiologically based computational framework was used to develop a novel gastric motility network model. Along with the widely assumed electrical gap junction coupling between the ICCs, we incorporated constitutive movement of second messengers, namely IP₃ and Ca²⁺ between ICC. We also included a rostro-caudal linear decreasing gradient of neural stimulus to the ICC along the length of the stomach to mimic enteric neurotransmitter release and a reverse increasing gradient of muscarinic receptor density.

Overall, this study provides us novel mechanistic understanding of the neurotransmitter release and its downstream action on emergent pathological slow waves observed in gastric motility disorders. The findings identify key cellular pathways involving second messengers and provide structural and mechanistic explanation for dysrhythmic slow waves and associated motility impairments of the stomach.

Identifier

FIDC010188

Recommended Citation

Ahmed, Md Ashfaq, "Functional and Dysrhythmic Slow Waves in the Stomach - An In Silico Study" (2021). FIU Electronic Theses and Dissertations. 4745.
https://digitalcommons.fiu.edu/etd/4745