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

尿路上皮是膀胱壁的内层，将尿液与下面的组织分开，作为一种调节膀胱饱满感的组织，它的作用最近引起了科学界的强烈兴趣。这一领域的一个重大进展是，当膀胱被拉伸时，尿路上皮细胞释放出一种化学信使三磷酸腺苷，这最终激活了感觉神经。这一机制的细节尚不清楚，但我们之前的工作发现了一种迄今未被研究的细胞成分，即所谓的肌成纤维细胞，它可能在这种感觉中发挥关键作用。我们希望验证这一假设，即尿路上皮和相关的肌成纤维细胞层，在尿路感染或炎症条件下可能积累的膀胱充盈和有害刺激下，形成一种感觉结构。我们将首先描述这些细胞结构对物理和化学刺激的反应，然后使用动物模型和人类样本来研究衰老对这些过程的影响。该项目将对中空器官的感觉功能和衰老过程提供新的见解；它还将确定分子靶点，根据这些靶点可以开发药物，以控制膀胱功能障碍时的膀胱活动。

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.