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Sensory dysfunction in the ageing bowel

Reference	BB/G015457/1
Principal Investigator / Supervisor	Professor David Grundy
Co-Investigators / Co-Supervisors	Dr Christopher Keating
Institution	University of Sheffield
Department	Biomedical Science
Funding type	Research
Value (£)	377,686
Status	Completed
Type	Research Grant
Start date	01/06/2009
End date	31/05/2012
Duration	36 months

Abstract

The overall aim of the project is to determine how ageing impacts on sensory signalling from the bowel. Our central hypothesis is that sensory signalling is attenuated with age as a consequence of neurodegenerative changes in the enteric nervous systems and the associated sensory signalling pathway. Specific objectives are to:- 1. determine how vagal and spinal afferent sensitivity to mechanical and chemical stimulation of the bowel is altered in young adults (3 months), middle age (12 months) and aged mice (24 months). 2. determine how enterochromaffin (EC) cell number and distribution and the bioavailability of 5-HT and ATP are altered in these animals and the impact this has for sensory signalling. 3. define the sensory mechanisms in tryptophan hydroxylase (TpH1) and 5-HT4 knockout mice as models of premature enteric ageing. A multidisciplinary approach will be employed combining electrophysiology and patch clamp recordings with a detailed examination of morphological and biochemical changes in 5-HT bioavailability along with an examination of 5-HT and ATP receptor expression in the bowel and sensory ganglia. Experimental approaches:- a. Direct electrophysiological recordings from sensory afferents supplying the proximal and distal bowel. b. Patch clamp recordings from identified gut projecting afferents c. Quantification of 5-HT and ATP release from the mucosal epithelium d. Histological characterisation of the distribution of sensory afferent endings in the gut wall e. Quantify the density and distribution pattern of EC cell in the mucosal epithelium f. Establishing the expression profile of serotonin synthesis and re-uptake by the mucosal epithelium We will also assemble a biobank of fresh and frozen tissue from animals with defined sensory phenotypes as a resource for the research community. These resources can be iteratively revisited in order to address emergent scientific questions using tools available to other investigators.

Summary

Within the wall of the gastrointestinal (GI) tract lies a complex network of neurones called the enteric nervous system (ENS). This network of nerves runs uninterrupted from the oesophagus to the anus. It is estimated to contain a similar number of neurones as that found in spinal cord (about 100 million) and serves to allow bowel function to be controlled and coordinated without influence from the central nervous system (CNS). Many parallels have been made between the CNS and ENS which has led to the latter being considered 'The Second Brain'. One thing that the ENS has in common with the CNS is that it undergoes age-related neurodegenerative changes that are in a number of ways comparable to neurodegenerative diseases like Alzheimer's. However, we know remarkably little about the mechanisms underlying the effect ageing has upon the enteric innervation and in particular sensory signalling from the gastrointestinal tract. The overall aim of the project is to determine how ageing impacts on sensory signalling from the GI tract and the mechanisms that underlie these changes. Our central hypothesis is that sensory signalling from the bowel is attenuated as the organism ages as a consequence of neurodegenerative changes in the enteric nervous system and associated sensory innervation. These leads to functional changes in sensory signalling arising from altered mediator release from the mucosal epithelium and altered receptor expression. To investigate this we will use mice of different ages that have been housed under identical conditions. We will thus be able to compare how the sensory neurons that innervate the gut respond to controlled mechanical and chemical stimulation in animals of different age. Young adults (3 months) will be compared to middle age mice (12 months) and aged animals (24 months). A number of key chemical mediators (including 5-HT and ATP) are stored in the intestinal mucosa are released upon bowel stimulation and in turn activate the sensory neurones. We will investigate how the cells that store these mediators change during ageing. We will measure the amount of mediator release and the receptors that the mediators act on on to mediate sensory signals. We will also utilize mice that have been genetically manipulated to alter these sensory signalling mechanisms. In particular mice lacking a specific receptor for 5-HT (called 5-HT4 receptor knockouts) will be studied because these animals have been shown to develop early enteric degenerative changes. We want to examine if sensory signalling is deficient in these animals. Similarly, another knockout that lacks an enzyme called tryptophan hydroxylase (TpH1) and does not synthesise 5-HT in the gut will be examined for a functional defect in its sensory signalling mechanisms. Therefore, this project aims to understand the mechanisms underlying changes in gastrointestinal afferent sensitivity that occur with ageing. A better understanding of these processes may eventually lead to therapies aimed at preventing or reversing these enteric neurodegenerative changes.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Ageing, Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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