Enteric infections and inflammation are often associated with disturbances in gastrointestinal motility and secretion. One of the common symptoms is diarrhea. Structural and functional alterations, which occur in the enteric nervous system and interstitial cell networks in these disease states, may lead to long term disturbances in intestinal function. In order to gain an understanding of how the neural networks are programmed to regulate muscle contraction and secretion, the following specific aims will be addressed in the colon of normal guinea pigs. The first is to determine the neural pathways that coordinate muscle contraction with secretion when the stimulus is mucosal stroking. Proposed studies focus on the afferent and efferent limbs of the reflex. They include determination of the role of endogenous and exogenous 5-HT in coordinating muscle contraction and secretion, on pharmacological drugs to evoke or uncouple synaptic transmission between submucosal and myenteric ganglia and on the neurochemical and electrophysiological identity of intrinsic afferent neurons.
The second aim i s to determine the neural pathways coordinating repetitive contraction and repetitive secretion when the stimulus is histamine. Planned studies include identification of the cellular structures mediating histamine's effects and analysis of the spread of excitation through neural and interstitial cell networks. Methodologies to be used include a brush mechanism, in an in vitro whole tissue preparation, to activate intrinsic neural reflexes while recording strain gauge tension and short circuit current simultaneously. These methods will complement in situ laser confocal imaging of living tissues and will be combined with electrophysiology, morphology, immunohistochemistry and retrograde labeling of neurons to obtain a spatial analysis of calcium signals throughout the enteric nerve plexus and network of interstitial cells. These novel approaches are expected to provide new information on interactions of the enteric nervous system and interstitial cell network with muscle and epithelial cells. These studies should provide new insights into integration of two diverse functions, muscle contraction and epithelial secretion, necessary for propelling and lubricating the intestinal contents. Furthermore, they may identify potential targets for the action of therapeutic drugs used in the treatment of diarrhea.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057016-05
Application #
6793975
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
2000-09-15
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
5
Fiscal Year
2004
Total Cost
$309,750
Indirect Cost
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Chen, Zhixiong; Suntres, Zach; Palmer, Jeffrey et al. (2007) Cyclic AMP signaling contributes to neural plasticity and hyperexcitability in AH sensory neurons following intestinal Trichinella spiralis-induced inflammation. Int J Parasitol 37:743-61
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Guzman, Jorge; Yu, Jun Ge; Suntres, Zacharias et al. (2006) ADOA3R as a therapeutic target in experimental colitis: proof by validated high-density oligonucleotide microarray analysis. Inflamm Bowel Dis 12:766-89
Cooke, Helen J; Xue, Jianjing; Yu, Jun Ge et al. (2004) Mechanical stimulation releases nucleotides that activate P2Y1 receptors to trigger neural reflex chloride secretion in guinea pig distal colon. J Comp Neurol 469:1-15
Christofi, Fievos L; Kim, Minsoo; Wunderlich, Jacqueline E et al. (2004) Endogenous adenosine differentially modulates 5-hydroxytryptamine release from a human enterochromaffin cell model. Gastroenterology 127:188-202
Raybould, H E; Cooke, H J; Christofi, F L (2004) Sensory mechanisms: transmitters, modulators and reflexes. Neurogastroenterol Motil 16 Suppl 1:60-3
Christofi, Fievos L; Wunderlich, Jacqueline; Yu, Jun Ge et al. (2004) Mechanically evoked reflex electrogenic chloride secretion in rat distal colon is triggered by endogenous nucleotides acting at P2Y1, P2Y2, and P2Y4 receptors. J Comp Neurol 469:16-36
Cooke, Helen J; Wang, Yu-Zhong; Wray, Dawn et al. (2003) A multi-tyrosinated sst1/2 receptor preferring somatostatin agonist inhibits reflex and immune-mediated secretion in the guinea pig colon. Regul Pept 114:51-60
Cooke, Helen J; Wunderlich, Jacqueline; Christofi, Fievos L (2003) ""The force be with you"": ATP in gut mechanosensory transduction. News Physiol Sci 18:43-9

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