NIA CO-FUNDING SCHEME: Nox enzymes in aging bladder dysfunction

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A normally functioning bladder is critical in maintaining the quality life of healthy ageing and disordered bladder (e.g., overactive bladders) is a major contributor to ageing-related suffering both physically and psychologically. Bladder disorders such as overactive bladders are extremely common in the aged population. In Europe 16.6% of the population aged 40 years and over suffer from symptoms of overactive bladders, reaching 30-40% for those aged 75 years and over. The symptoms include unpleasant and intense urge to pass urine, and unwanted leak of urine, often unpredictable and stressful. These chronic conditions affect healthy ageing and significantly reduce the quality of life. They not only impose a huge cost to the medical care service (about 2% of NHS budget) but also financial and social burden to the community. Atpresent the causes underlying these disorders of the ageing bladder are not known, largely due to a paucity of basic research into the control of bladder function, in particular in relation to ageing.Bladder is a hollow organ with a muscle (smooth muscle) layer in the middle, covered by a tissue sheet and lined up with a mucosa layer - the urothelium. The muscle is relaxed to hold urine and contracts to expel urine when bladder is full. These activities are controlled by the nerves to sense the bladder fullness (sensory nerve) and those to tell the muscle to contract (motor nerve). However, how precisely bladder fullness is detected by the sensory nerves is poorly understood. A significant advance in our understanding of bladder function is the novel role of urothelium. Previously considered as passive barrier, urothelium has recently been discovered to be able to "sense" bladder fullness by releasing active chemicals to activate the sensory nerves in response to bladder distension by filled urine. As it is different from the underlying smooth muscle, it serves an ideal drug target to control excessive sensory stimulations without affecting normal muscle function. The bottle neck for further progress is how urothelium function is regulated. Crucially what are the urothelium-derived factors that make ageing bladders prone to over-activity.Our unpublished pilot studies show that urothelium generates reactive oxygen species - chemically active molecules capable of causing oxidative damage. The tissue can produce excessive amount of these molecules in response to pathological conditions, e.g. inflammation, diabetes as well as ageing. Excessive reactive oxygen species will then cause tissue damage and organ dysfunctions. These pilot data also indicate that excessive production of reactive oxygen species from urothelium is involved in bladder ageing and dysfunction. However, the source of excessive generation of reactive oxygen species in the bladder is unknown. One enzyme that specifically generates reactive oxygen species is the Nox2 which has been found to be responsible for organ dysfunction in many tissues. Our pilot data further suggest an action of Nox2-derived reactive oxygen species via deteriorating urothelium bio-sensing and in turn affecting bladder function in ageing.We hypothesize that Nox-derived reactive oxygen species and oxidative damage have a significant role in urothelium and ageing-related bladder dysfunction and other disorders. In this joint UK-US project, we aim to understand the role of Nox and reactive oxygen species in regulating bladder function and how Nox is activated in ageing bladder while our US collaborators will focus on pathological bladders. We will perform a set of extremely important experiments to achieve these aims. This project will lead to a new direction of research into the newly-recognised sensory structure urothelium and provide new insights into bladder ageing. It will also provide added translational value for application of novel specific Nox2 inhibitors in improving ageing bladder function and treating bladder disorders.