The striking motor disturbances that accompany inflammatory bowel disease (IBD) reflect a dynamic interplay between inflammatory mediators and the enteric nervous system. While it is clear that inflammatory mediators trigger enteric neuronal responses, their precise targets and mechanisms of action are unknown. The proposed studies are designed to elucidate how inflammation modulates the afferent components of the reflex circuitry of the bowel, namely the enterochromaffin (EC) cells and AH neurons. We will test the hypothesis that colitis is associated with an increase in the availability of serotonin (5-HT) from EC cells and increased excitability of AH neurons, and that these changes are mediated by prostaglandins generated by cyclooxygenase 2 (COX-2). To test this hypothesis, we will use the thoroughly validated trinitrobenzene sulfonic acid (TNBS) model of colitis in the guinea pig. In the first specific aim, we will evaluate the availability of 5-HT from EC cells in the inflamed colon by quantifying the 5-HT-immunoreactive EC cell population, mucosal 5-HT levels, stimulus-induced 5-HT release, and 5-HT uptake by the mucosa of the inflamed colon.
In Specific Aim 2, we will test whether colitis is associated with an increase in the excitability of AH neurons, leading to an increase in the activation of these cells in response to physiological stimuli. The excitability of AH neurons will be investigated by evaluating their electrical properties and their sensitivity to 5-HT. Furthermore, activation of AH neurons by mucosal stimulation will be evaluated (1) electrophysiologically, (2) with the activity marker, FM2-10, (3) by measuring release of calcitonin gene-related peptide, and (4) by measurement of propulsive motor activity. The third specific aim will test whether changes in EC cell and AH neuron function, that are induced during inflammation, are initiated by prostaglandins derived from the induction of COX-2. To accomplish this, we will test whether prostaglandins mimic the effects of inflammation on EC cells and on AH neurons, and we will test whether the neuroendocrine effects of TNBS-induced colitis are attenuated by blockade of COX-2. The results of these studies will reveal how inflammation and prostaglandins alter the function of the afferent components of enteric neural circuits. This information will advance our understanding of the mechanisms of neuro-immune integration and motility disturbances that are associated with IBD, and may lead to novel therapeutic approaches for restoring motor function to normal levels in individuals with IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK062267-01
Application #
6532078
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
2002-07-12
Project End
2005-06-30
Budget Start
2002-07-12
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$289,365
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
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