The prevalence of bladder diseases significantly increases with age, with one third of adults over 65 suffering from urinary incontinence. Although incontinence is not life threatening, it can often lead to significant anxiety, social isolation and a loss of dignity. The bladder is a complex organ, which consists of many layers (Figure 1). The bladder is connected by neuronal signalling pathways of the autonomic nervous system that communicate with the smooth muscle layers to drive muscular contraction and aid distention. One key layer is the urothelium, which forms an essential barrier between the bladder luminal content and the underlying vasculature, connective, nervous and muscular tissues. The urothelium has been shown to play a pivotal role in the regulation of various key functions of the bladder through signalling by urothelial chemical transmitters (UCT, Figure 1).
Such UCT include acetylcholine (ACh), adenosine triphosphate (ATP) and nitric oxide (NO). These UCT have been shown to be involved in regulating muscular tone, driving distension and regulating visceral hypersensitivity. However, little is known about these UCT alter with age and specifically relate to the functional deficits observed with age. Our hypothesis is that urothelium signalling mechanisms are reduced with age, leading to a loss in the regulation of bladder contractility that presents as age-related bladder dysfunction. Our aim is to explore how signalling is altered with age in the bladder though a variety of methodologies.
Objective 1: To develop a novel sensor for monitoring of urothelium signalling molecules. We will focus on the development of specific robust sensing approaches for the rapid determination. Varying approaches towards molecular specificity for detection of urothelium signalling molecules will be approaches using enzymatic and RNA aptamer approaches. Such molecular recognition approaches will be utilised to provide high specificity and will be interfaced with electrochemical sensors for monitoring such that measurement from tissue or in a clinical environment can be conducted in real-time. Novel approaches to sensor fabrication as well as detection methodologies will be explored.
Objective 2: Understand how UCT change with age. Studies will be carried out to monitor how levels of the UTC are altered with age. Measurements will be conducted using the sensor developed to monitor the level of UTC present and released from young and old aged mice. Pharmacological agents will be utilised to understand how they augment the release of UTCs and therefore provide insight into the signalling capabilities and changes with ageing. We will conduct biochemical assays to further characterise the mechanism, where the level and expression of enzymes and molecular targets of UTC in young and old bladder tissue will be measured. To understand how UTC changes relate to the functional changes with age. We will conduct functional studies from isolated bladder strips and explore the role of urothelium. Contractility studies will be correlated with the changes observed with age in both tissue samples in the presence and absence of the urothelium. Such studies will provide insight into the role of the urothelium with age and its connection to the base contractility issue. These studies will be translated to characterise the ageing human bladder, where identical measurements on shed cells present in patients’ urine will be conducted. The student will correlate findings with clinical measures to study bladder function, the potential influence of medication and the control of this process by the brain.