Neurons in the wall of the intestine control how the gut reacts to an ingested meal;they also regulate the processes of digestion, nutrient absorption, and waste elimination. In inflammatory bowel disease (IBD), various features of gut function, including motility, secretion and sensitivity are altered. As nerve cells of the bowel regulate all of these functions, it is likely that changes in these neurons cause the symptoms that lead to the suffering experienced by afflicted individuals. In the past 3 years, we have evaluated inflammation- induced changes along the circuitry of the colon in a step-wise fashion, and we have identified fundamental changes at three sites in particular: (1) increased serotonin availability in the mucosal layer;(2) intrinsic sensory neuron hyperexcitability;and (3) facilitation of synaptic signals between neurons. The proposed experiments are designed to elucidate the mechanisms that underlie these changes, how these changes affect colonic motility, and what changes persist following recovery from inflammation.
In specific aim 1, we will use electrophysiology and molecular approaches to test the hypothesis that intrinsic sensory neuron hyperexcitability involves down-regulation of intermediate conductance, Ca2+-activated K* channels and an up-regulation of hyperpolarization-activated cation channels.
In specific aim 2, we will use electrophysiology and electron microscopy to investigate the mechanisms of synaptic facilitation by testing for changes in presynaptic neurotransmitter release, postsynaptic sensitivity and nerve terminal density in the myenteric plexus.
In specific aim 3, we will study colonic peristalsis, spatiotemporal motility patterns and neuromuscular responses to determine which inflammation-induced changes in the reflex circuitry contribute to altered colonic motility and how this occurs.
In specific aim 4, we will test whether inflammation-induced neuroplasticity and related changes in motility persist beyond recovery from inflammation. Such changes would be undetectable by standard diagnostic procedures, and could underlie altered gut function during remission from inflammatory bowel disease and in post-inflammatory irritable bowel syndrome (IBS). An array of techniques will be used, including intracellular voltage and current recordings, real time quantitative polymerase chain reaction, electron microscopy, and digitally enhanced motility assays. In this way, we will provide a unique, integrated/translational view of neurotransmission in the inflamed colon. The findings of these investigations, all of which are highly feasible, will enhance our understanding of the pathophysiology of the inflamed colon, and they will improve our comprehension of IBS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062267-07
Application #
7750538
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
2002-07-12
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
7
Fiscal Year
2010
Total Cost
$272,083
Indirect Cost
Name
University of Vermont & St Agric College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Spohn, Stephanie N; Mawe, Gary M (2017) Non-conventional features of peripheral serotonin signalling - the gut and beyond. Nat Rev Gastroenterol Hepatol 14:412-420
Yusta, Bernardo; Matthews, Dianne; Flock, Grace B et al. (2017) Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway. Mol Metab 6:503-511
Vanner, Stephen; Greenwood-Van Meerveld, Beverley; Mawe, Gary et al. (2016) Fundamentals of Neurogastroenterology: Basic Science. Gastroenterology :
Spohn, Stephanie N; Bianco, Francesca; Scott, Rachel B et al. (2016) Protective Actions of Epithelial 5-Hydroxytryptamine 4 Receptors in Normal and Inflamed Colon. Gastroenterology 151:933-944.e3
Mawe, Gary M; Sharkey, Keith A (2016) The Intrinsic Reflex Circuitry of the Inflamed Colon. Adv Exp Med Biol 891:153-7
Woods, Stephanie E; Leonard, Monika R; Hayden, Joshua A et al. (2015) Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous ""black"" pigment gallstone formation in germfree Swiss Webster mice. Am J Physiol Gastrointest Liver Physiol 308:G335-49
Mawe, Gary M (2015) Colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colon. J Clin Invest 125:949-55
Camilleri, M; Drossman, D A; Becker, G et al. (2014) Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterol Motil 26:1386-95
Balemba, Onesmo B; Stark, Timo D; Lösch, Sofie et al. (2014) (2R,3S,2'' R,3''R)-manniflavanone, a new gastrointestinal smooth muscle L-type calcium channel inhibitor, which underlies the spasmolytic properties of Garcinia buchananii stem bark extract. J Smooth Muscle Res 50:48-65
Sharkey, Keith A; Mawe, Gary M (2014) Neurohormonal signalling in the gastrointestinal tract: new frontiers. J Physiol 592:2923-5

Showing the most recent 10 out of 53 publications