Intestinal inflammation leads to changes in a variety of functions, including motility, secretion and sensitivity. Neural circuits of the bowel regulate ll of these functions, and it is likely that changes in these reflex circuits contribute to the symptos suffered by afflicted individuals. In the past 8 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 several sites, including: (1) increased serotonin availability in the mucosal layer;(2) intrinsic sensory neuron hyperexcitability;(3) facilitation of synaptic signals between neurons;and (4) attenuated inhibitory purinergic neuromuscular transmission. Furthermore, we have elucidated the mechanisms that underlie many of these changes, determined what changes persist following recovery from inflammation, and linked changed in neural function to altered motility patterns. In this grant application, we are proposing to build upon our findings and those of others to examine novel mechanisms by which gut functions and bone density can be affected by inflammation, and explore innovative approaches to prevent or reverse these changes and to minimize mucosal damage during the inflammatory response.
The first aim of this grant application is designed to test the hypothesis that the inflammation- induced decrease in purinergic neuromuscular transmission involves a decrease in purine synthesis and release as the result of oxidative stress damage to mitochondria in the muscular is of the inflamed colon. Experiments proposed in the second aim is based on our recent discovery that 5-HT4 receptors (5HT4Rs) are highly expressed in the colonic epithelium, and that activation of these receptors induces 5-HT, mucus, and Cl- secretion, and promotes propulsive motility. We will test the hypothesis that activation of 5-HT4Rs on cells in the epithelial lining has a protective effect, attenuating the severity of colitis and protecting colonc motor function.
Specific aim 3 is based on the knowledge that various forms of intestinal inflammation are associated with decreased bone density, and the recent discovery that circulating gut-derived serotonin has a negative impact on bone formation. We will test the hypothesis that the inflammation-induced increase in mucosal serotonin availability contributes to the decrease in bone density, and that these effects can be reduced by modulating mucosal serotonin signaling or by inhibiting the 5-HT1B receptor, which is expressed by pro-osteoblasts. This proposal involves an integrated approach, using state-of-the-art techniques, to investigate novel concepts related to the neuromuscular and serotonin signaling in the gut, and to examine a potential damaging relationship between mucosal serotonin and bone integrity. The findings of these studies will greatly improve our understanding of purinergic neuromuscular transmission and mucosal serotonin signaling in the gut.

Public Health Relevance

Gastrointestinal (GI) disorders, including Crohn's Disease and ulcerative colitis, are extremely common. They cause a great deal of suffering and are very costly to the healthcare system and society. There is a pressing need to gain a better understanding of how and why gut functions and sensation change in response to inflammation, and how to prevent these changes from occurring. The proposed studies will involve the use of animal models and human tissues to investigate the mechanisms of changes in intestinal serotonin signaling and neuromuscular transmission that occur in the inflamed colon. Our studies will test the hypothesis that treatment strategies targeting free radicals and specific serotonin receptors could dampen the extent of the inflammatory response, and prevent associated damage to gut functions and bone density.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK062267-08A1
Application #
8505618
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Hamilton, Frank A
Project Start
2002-07-12
Project End
2017-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$340,606
Indirect Cost
$114,188
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
Sharkey, Keith A; Mawe, Gary M (2014) Neurohormonal signalling in the gastrointestinal tract: new frontiers. J Physiol 592:2923-5
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
Roberts, Jane A; Durnin, Leonie; Sharkey, Keith A et al. (2013) Oxidative stress disrupts purinergic neuromuscular transmission in the inflamed colon. J Physiol 591:3725-37
Mawe, Gary M; Hoffman, Jill M (2013) Serotonin signalling in the gut--functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 10:473-86
Gulbransen, Brian D; Bashashati, Mohammad; Hirota, Simon A et al. (2012) Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nat Med 18:600-4
Hons, I M; Storr, M A; Mackie, K et al. (2012) Plasticity of mouse enteric synapses mediated through endocannabinoid and purinergic signaling. Neurogastroenterol Motil 24:e113-24
Hoffman, Jill M; Tyler, Karl; MacEachern, Sarah J et al. (2012) Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142:844-854.e4
Hoffman, J M; McKnight, N D; Sharkey, K A et al. (2011) The relationship between inflammation-induced neuronal excitability and disrupted motor activity in the guinea pig distal colon. Neurogastroenterol Motil 23:673-e279
Wood, Michael J; Hyman, Neil H; Mawe, Gary M (2010) The effects of daikenchuto (DKT) on propulsive motility in the colon. J Surg Res 164:84-90
Costedio, Meagan M; Coates, Matthew D; Brooks, Elice M et al. (2010) Mucosal serotonin signaling is altered in chronic constipation but not in opiate-induced constipation. Am J Gastroenterol 105:1173-80

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