Institute of Biological and Biomedical Sciences

John Young

Little is known about the origins and subsequent development of diseases that cause urinary incontinence. One such disease is over-active bladder, which is affects around 1 in 6 men and 1 in 4 women. The prevalence increases with age and with populations ageing, it is estimated that 20% of the world population will have OAB in 6 years. Despite the large proportion of society affected by this debilitating condition, and its associated costs to the health service, insurers and the individual, we know next to nothing about how over-active bladder develops. Research in the Young lab seeks to characterise the origins and progression of over-active bladder so as to discover new drug targets and therefore improve treatment outcomes; ultimately lowering the impact on the individual and the burden on society.

For further details and publication history please see my staff profile

OUR CURRENT LABORATORY RESEARCH

AgeUK Research Fellowship: to characterise non-responsiveness to first-line over-active bladder treatment

In 2010, Dr Young was awarded an AgeUK Research Fellowship to investigate why the first-line treatment for over-active bladder - a class of drugs called anti-muscarinics - do not work for around of half of over-active bladder patients. The research phase of the study was completed at the end of March 2013, and results will be published very soon. Briefly, Dr Young focussed on the sensory mechanism our bladder uses to tell the brain when our bladder is nearly full. This mechanism is thought to be modified in people with over-active bladder, giving them a false message that their bladder is full when it is not; a perception of urgency to urinate.

How anti-muscarinics work

Despite being used clinicially as the first line treatment for over-active bladder for many decades, the mode of action of anti-muscarinics has only recently been characterised. A study on humans showed an improvement on symptoms associated with filling of the bladder, rather than its voiding - with an increase in bladder capacity, for example - suggesting an effect of anti-cholinergics on the sensation of bladder volume. Experiments recording sensory nerve activity confirmed this hypothesis. Following on from this, Dr Young and colleagues went on to demonstrate how anti-cholinergics impair signalling from the bladder's lining, the urothelium. Ordinarily, stretch of the urothelium causes release of a neurotransmitter, ATP, from the urothelium. Dr Young demonstrated that anti-cholinergics prevent ATP release; suggesting that another neurotransmitter, acetylcholine, is initially released which, in turn, stimulates release of ATP.

mode of action of anti-muscarinics

Characterising the healthy signalling pathway is an important first step in understanding what might be affected in bladder diseases that are characterised by heightened bladder sensation - such as over-active bladder and interstitial cystitis. Likewise, by having characterised how the normal signalling pathway is blocked by anti-muscarinic drugs used for over-active bladder is of great importance to then going on to understand why some people do not respond to this medication - are certain parts of the pathway somehow different in the people that do not respond to medication?

The underactive bladder

A significant number of the elderly report of urinary retention - but without an accompanying restriction of flow, such as bladder outlet obstruction caused by an enlarged prostate in men. Patients often have greatly increased bladder capacities, weak flows and thus urinary retention and associated urinary tract infections. As part of an EU funded collaboration (www.incomb.eu), Dr Young investigated the basis of this disease with colleagues at the University of Surrey, Queen's University, Belfast, and Pfizer. Underactive bladders were characterised by a loss of nerves and a type of cell called interstitial cell; that exist in the space between the bladder wall's muscle and its lining, perhaps playing a role in bladder contractions (for more details see Johnston et al. 2012 J. Cell. Mol. Med. 16:1533-1543). Surprisingly, bladder contractions were not reduced in the underactive bladder group. The basis for urinary retention may be in the observation that bladder walls were less rigid and relaxed more easily, pointing towards changes in the matrix of proteins that comprises the bladder wall (Young et al. 2013 BJU Int.111:355-61). As such, underactive bladder symptoms may be alleviated with the prescription of a drug to improve contractions.