Integrated analysis of the impact of age-associated neuronal and enteroendocrine changes on normal bowel functions

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In the ageing population, terminal bowel dysfunction, manifest as faecal incontinence, which is often linked with faecal impaction, is very common and a significant cause of morbidity. Normal bowel function and defecation depend upon involuntary actions of the terminal colon, rectum and internal anal sphincter, and voluntary control of the external anal sphincter and pelvic floor muscles. These processes, in turn, depend upon the structural integrity and the normal molecular and physiological properties of the complex system of nerves, muscles and secretory cells that together make up this part of the digestive tract. Many cells and tissues are known to undergo structural and molecular changes during ageing that result in changes to their functional properties. Little is known however, of the changes that occur in the cells of the terminal bowel during ageing. The aim of the proposed project is therefore to use a multi-disciplinary approach, bringing together expertise from four academics, to fully characterise the physiological, molecular and structural age-associated changes in the cells of the terminal colon, rectum and anal sphincters. The work will be performed in mice, for a number of reasons; mice have a life-span amenable to studies on ageing; many of the variables associated with studies on humans can be avoided; mouse gastrointestinal physiology is well-understood and readily analysed and in future, research based on the data obtained from this project will be able to employ the powerful tool of mouse genetics to further analyse the changes that occur in ageing terminal bowel. The results of this work will allow more effective therapies for the treatment of age-associated incontinence and faecal impaction to be developed