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

在老龄化人口中，终末期肠道功能障碍，表现为大便失禁，这往往与粪便嵌塞有关，是非常常见的，也是发病率的重要原因。正常的肠道功能和排便依赖于末端结肠、直肠和内肛门括约肌的非自主动作，以及对肛门外括约肌和盆底肌肉的自愿控制。这些过程反过来又依赖于组成消化道这一部分的神经、肌肉和分泌细胞组成的复杂系统的结构完整性和正常的分子和生理特性。众所周知，许多细胞和组织在老化过程中会经历结构和分子的变化，从而导致其功能特性的变化。然而，人们对终末肠道细胞在衰老过程中发生的变化知之甚少。因此，拟议项目的目的是使用多学科方法，汇集四位学者的专业知识，全面描述末端结肠、直肠和肛门括约肌细胞的生理、分子和结构随年龄的变化。这项工作将在小鼠身上进行，原因有很多；小鼠的寿命容易受到衰老研究的影响；许多与人类研究相关的变量可以避免；小鼠的胃肠道生理学很容易被理解和分析，未来，基于这个项目获得的数据的研究将能够利用小鼠遗传学这一强大的工具来进一步分析衰老终末肠道中发生的变化。这项工作的结果将为年龄相关性大小便失禁和粪便嵌塞的治疗提供更有效的治疗方法。

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