Doctor of Philosophy (PhD)
First Advisor's Name
Dr. Ranu Jung
First Advisor's Committee Title
Second Advisor's Name
Dr. James Abbas
Second Advisor's Committee Title
Third Advisor's Name
Dr. Lidia Kos
Third Advisor's Committee Title
Fourth Advisor's Name
Dr. Jacob McPherson
Fourth Advisor's Committee Title
Fifth Advisor's Name
Dr. Jessica Ramella Roman
Fifth Advisor's Committee Title
Sixth Advisor's Name
Dr. Sharmila Venugopal
Sixth Advisor's Committee Title
Slow-wave, gastric motility, entrainment, coupled oscillators, gap junction, IP3, gap junction blocker, endogenous neurotransmitter, Acetylcholine
Date of Defense
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.
Ahmed, Md Ashfaq, "Functional and Dysrhythmic Slow Waves in the Stomach - An In Silico Study" (2021). FIU Electronic Theses and Dissertations. 4745.
Available for download on Wednesday, June 14, 2023
Bioelectrical and Neuroengineering Commons, Biological Engineering Commons, Systems and Integrative Engineering Commons
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