Mode of action of sensory transmitters in bladder urothelium and the effect of ageing

The role of urothelium, the inner lining of the bladder wall that separates urine from underlying tissues, has recently generated intense interest in the scientific community as a tissue that mediates the sensation of bladder fullness. A significant advance in this area was the demonstration of release of a chemical messenger, ATP, from the urothelium when the bladder is stretched, as occurs during filling, and which eventually activates sensory nerves. The details of this mechanism are unclear, but our previous work identified a hitherto uninvestigated cellular fraction, so-called myofibroblasts, that may have a key role in this sensation. We wish to test the hypothesis that the urothelium, and the associated myofibroblast layer, form a sensory structure in response to bladder filling and harmful stimuli as may accumulate during urinary tract infections, or inflammatory conditions. We will first characterise the responses of these cell structures to physical and chemical stimuli and then investigate the effect of ageing on these processes, using both animal models and human samples. The project will provide novel insights into sensory function of hollow organs and processes of ageing; it will also identify molecular targets from which drugs may be developed to control bladder activity when it becomes dysfunctional.

Recently, the role of the urothelium has generated significant interest as a site of bladder sensation. A key advance was the demonstration of ATP release from the urothelium upon bladder distension, which eventually activates afferent nerves. However, the intermediate processes in this sensory transduction process are unclear. Our previous work suggests that a suburothelial myofibroblast network interacts with the urothelial layer to transmit and amplify the ATP response. We wish to test the hypothesis that the urothelium, and the associated suburothelial myofibroblast layer, form the sensory structure in response to bladder filling and noxious stimuli. Furthermore, we propose that the system is upregulated in the ageing bladder and that this may underlie the increased prevalence of heightened sensory responses in the elderly. We will first characterise the responses of these cellular elements to physical and chemical stimuli and then quantify the changes that occur in the ageing bladder, using both animal models and human samples. The project will permit novel insights into visceral sensory transduction and process of ageing, as well as identify molecular targets for control of bladder function.