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

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. At
present 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Our unpublished pilot studies show that urothelium generates reactive oxygen species - chemically active molecules capable of causing oxidative damage.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.

A normally functioning bladder is critical in maintaining the quality of life and healthy ageing and disordered bladder such as the overactive bladder is a major contributor to ageing-related suffering. However, the mechanisms of bladder dysfunction are poorly understood and factors that predispose the ageing bladder to over-activity are unknown. Urothelium, a newly discovered sensory structure, regulates significantly bladder function and its distinct receptor profile different from the underlying smooth muscle makes it an ideal therapeutic target to control sensory activation with little side-effect on smooth muscle function. Urothelium generates ROS and is susceptible to oxidative damage. However, the mechanism of redoxregulation of urothelium function and the enzymatic source of ROS generation in the bladder are poorly understood. Our pilot data have discovered an age-related up-regulation of Nox2 in the vasculature-rich urothelium and more importantly ROS causes major damage in bladder function during ageing.

We hypothesize that Nox has a significant role in urothelial function and is involved in ageing-related bladder disorders. The overall aim of this collaborative UK-US project is to investigate the role of Nox and ROS in regulating bladder function and the mechanism of Nox activation and oxidative damage of ageing bladder (UK remit) and pathological bladders (US focus).

This is the first study to examine the role of Nox and ROS in urothelial function. The outcomes of this project will provide
new insights into the mechanisms of urothelium regulation of bladder function and oxidative stress in bladder ageing. It will
also provide added translational value for novel specific Nox2 inhibitors in improving ageing bladder function.

Addressing a key priority area identified by the BBSRC - the ageing bladder, the outcomes of the project have a wide social, health and economical impact.

1. Scientists and pharmaceutical industry
Understanding the control of bladder function is a critical area of biomedical research with the challenge of the increasing ageing population and ageing-associated bladder dysfunctions. The discovery of the urothelium as a novel sensory structure offers an opportunity for specific targeting the urothelium with little side effect on the normal smooth muscle function. By exploration of ROS and Nox enzyme and their roles in regulating urothelium and bladder function in ageing and pathological bladders, this project will provide novel insight into bladder physiology, ageing and pathophysiology of bladder over-activity. These will be of great interest to scientists in bladder and ageing research, and ROS biology. The outcomes will not only provide scientific basis for the pharmaceutical industry to develop new therapies by targeting the Nox pathways, it will also pave the way for investigating the therapeutic potential of the recently developed Nox2-specific inhibitors. We will disseminate our findings through national and international conferences and premium journals of the field, in particular via the open access. We will continue and develop our link with the pharmaceutical industry and collaborations.

2. Society, health professionals and the NHS
Bladder disorders such as bladder over activity are extremely common in the aged population, in particular with advanced ageing. These chronic conditions affect healthy ageing, and significantly reduce the quality of life for the elderly. They not only impose a huge cost to the medical care service (about 2% of NHS budget) in managing their symptoms but also enormous financial and social burden to the community. At present the causes underlying disorders of the ageing bladder are not known, largely due to a paucity of basic research into the control of contractile function in the lower urinary tract, in particular in relation to the process of ageing. The outcomes on ROS and Nox regulation in the urothelium will not only provide new drug targets for bladder dysfunction that could be exploited by pharmaceutical industry, subsequent investigation on the Nox2 specific inhibitors will offer real prospect of its application by health care professionals for the management of symptoms in the ageing population to improve their quality of life. We will share information on novel management care pathways and our own insight into the pathological basis of these disorders, the effectiveness of the novel inhibitor in controlling ROS mediated bladder dysfunction with clinicians through workshops and local, national and international clinical meetings, as well as visit to local hospitals to speak to the health professionals and NHS R&D staff.

3. Patients and carers (US focus)
New knowledge and management strategies as a result of this research are likely to be great interest to the patients and carers in the community, in particular the therapeutic potential of the novel Nox2 inhibitors will directly benefit the patients and be of specific interest to carers. We will reach out to patients and carers by reporting our findings in Surrey Net News and newspapers.

4. Policy makers, media and the public
New information generated from this project on ROS, Nox, their roles in health and diseases, targeting Nox, new ways of managing age-related disorders, will also be of keen interest to media and policy makers and educational to the general public. We will reach out to them through public engagement, for example, the media, TV interviews.