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Neurochemicals In The Control Of Human Bladder Function
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
The problem of urinary incontinence has received little attention from the medical and scientific research community until the last 10-15 years. Urinary incontinence can cause severe distress and is a taboo subject, even though it affects 30-40% of women. Public figures speak out about their experiences with breast cancer or heart disease, but not about leakage of urine. Elderly people with incontinence are forced into nursing homes, with major costs to the community. Incontinence is a major cli ....The problem of urinary incontinence has received little attention from the medical and scientific research community until the last 10-15 years. Urinary incontinence can cause severe distress and is a taboo subject, even though it affects 30-40% of women. Public figures speak out about their experiences with breast cancer or heart disease, but not about leakage of urine. Elderly people with incontinence are forced into nursing homes, with major costs to the community. Incontinence is a major clinical problem: although over 800 new patients per annum are seen at our Pelvic Floor Unit, the waiting time for a first appointment is 14-15 weeks. There are four main types of urine leakage: - stress incontinence (weak pelvic floor muscles); - overflow incontinence (seen in men with prostatic hypertrophy); - sensory urgency (frequent, uncomfortable desire to urinate); and - detrusor instability (bladder muscle spasms with leakage). We are primarily interested in detrusor instability and sensory urgency, which cause 35% of incontinence in general, but up to 85% of cases in the elderly. Patients suffer from an urgent desire to visit the toilet frequently, and may leak urine if they cannot reach the toilet quickly. Unlike stress incontinence, it cannot be corrected by pelvic floor surgery. Drug treatment is often unsuccessful, with many unacceptable side effects. In our research group, we have found that the sensory nerve which convey the sensation of bladder fullness, are overabundant and display increased amounts of neurochemicals. Our studies in isolated bladder muscle from these patients have shown abnormalities in responsiveness. Thus bladder from women with urge incontinence is resistant to drugs which abolish contraction in normal bladder. In this project we plan to find out why such changes occur. We will use new techniques to study bladder nerves and the receptors which convey the message to contract the bladder muscle.Read moreRead less
Non-neuronal ATP: Regulation Of Release And Action In The Bladder
Funder
National Health and Medical Research Council
Funding Amount
$451,553.00
Summary
Incontinence disorders are costly and debilitating. How the bladder signals the normal sensation of fullness as well as the urgent need to void urine (urgency) is still not fully understood. The signaling molecule ATP is released during bladder stretch. Using animal and human bladder, we will study how the bladder lining is involved in this signaling process, by measuring how bladder chemicals interact with stretch to modulate ATP release, and how ATP can influence nerve impulses to the brain.
Sensory Mechanisms In Normal Bladder And In Cystitis
Funder
National Health and Medical Research Council
Funding Amount
$408,861.00
Summary
The function of the lower urinary tract is to store urine and release it at appropriate times. This requires neural circuits in the brain, spinal cord and peripheral ganglia. When the bladder fills, sensory neurones fire and activate these neural circuits to store urine or to empty the bladder. If sensory neurones are too easily excited (a process called sensitisation ) this will lead to clinical disorders, including the common painful bladder syndromes, whose cause is not known (interstitial cy ....The function of the lower urinary tract is to store urine and release it at appropriate times. This requires neural circuits in the brain, spinal cord and peripheral ganglia. When the bladder fills, sensory neurones fire and activate these neural circuits to store urine or to empty the bladder. If sensory neurones are too easily excited (a process called sensitisation ) this will lead to clinical disorders, including the common painful bladder syndromes, whose cause is not known (interstitial cystitis, sensory urgency etc). These are characterised by pelvic pain, urinary urgency, frequency and, in some cases, urge incontinence (loss of urine for no apparent reason) which results from unstable or overactive bladder. Despite a large database of knowledge about the sensory innervation of the bladder, many important gaps still exist. These gaps have restricted the development of new therapies. For example, we have little idea about exactly which functional classes of sensory neurones signal filling of the normal bladder or what different types of information they carry. This is vital information for understanding which neurones are affected in disease states and whether they are all affected in the same way. We have developed new methods that will allow us to identify the major classes of sensory neurones that innervate the bladder, what they respond to and how they are activated. We will also determine whether some classes are preferentially sensitised by inflammation and the most important mechanisms that are likely to underlie this. The significance of this project is that it provides the basic scientific understanding of sensory innervation of the bladder and will identify potential targets for selective pharmacological intervention in common bladder disorders.Read moreRead less
Sacral Parasympathetic Innervation Of Distal Bowel
Funder
National Health and Medical Research Council
Funding Amount
$314,983.00
Summary
Not a topic for polite conversation, normal movements of the colon and rectum are essential for good health and a sense of wellbeing. Constipation, diarrhoea, incontinence and pain result from disordered motility. One major control mechanism is the parasympathetic innervation. While we know of its importance, how it works in health and diseases is poorly understood. This project will use state-of-the-art techniques to study this pathway in order to understand its role in health and disease
Lifestyle And Pharmacological Regulation Of Lipoprotein Metabolism In The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$504,504.00
Summary
Visceral obesity is an increasing problem in Australia. Elevated blood fat levels are associated with visceral obesity and increased risk for heart disease. Effective management of lipid disorders is important to reduce the risk for heart disease. Fats in the blood originate from dietary sources and from synthesis by the liver. In viscerally obese subjects, the level of blood fats is elevated compared with lean individuals. These abnormalities are partly caused by overproduction of fat in the li ....Visceral obesity is an increasing problem in Australia. Elevated blood fat levels are associated with visceral obesity and increased risk for heart disease. Effective management of lipid disorders is important to reduce the risk for heart disease. Fats in the blood originate from dietary sources and from synthesis by the liver. In viscerally obese subjects, the level of blood fats is elevated compared with lean individuals. These abnormalities are partly caused by overproduction of fat in the liver and impaired clearance of fat from the blood. Two particular proteins, called apolipoprotein A and B-100, are important fat carriers responsible for transporting fat in the blood. Viscerally obese subjects have abnormal levels of these apoproteins and we hypothesised that they are responsible for the impaired movement of fat in the blood. Viscerally obese subjects are insulin resistant and are prone to diabetes. This condition will impair the regulation of apolipoproteins A and B-100. In this research project, we will investigate the effect of a fibrate (a regulator of fat production and breakdown) and ezetimibe (a regulator of dietary cholesterol absorption) on the production and clearance rates of apolipoprotein A and B in a group of obese subjects who are on weight loss program . If our hypothesis is correct, these studies will demonstrate new mechanisms of action of the two drugs that will complements the favourable effect of weight loss in the treatment of elevated blood fats and reduction in risk of heart disease in an important groups of subject in the population.Read moreRead less
Mechanisms Of Activation Of Vascular Afferent Nociceptors To The Gut
Funder
National Health and Medical Research Council
Funding Amount
$542,890.00
Summary
We have recently identified the nerve fibres responsible for detecting pain from the gut. In this project we will study exactly how these nerve cells are activated by movements of the gut wall, by changes in blood vessel diameter and how this can be studied most efficiently We will use this information to develop simple preparations in which to study these sensory nerves in animal and adult tissue to test which drugs may affect their excitability and hence be useful in treating gut pain.
Plasticity And Regeneration Of Bladder Motor Nerve Circuits After Injury
Funder
National Health and Medical Research Council
Funding Amount
$333,313.00
Summary
Our goal is to determine ways of improving the recovery of bladder-controlling nerves after they are injured, which has devastating effects on bladder function. This can happen because of lumbosacral spinal nerve damage or pelvic surgery. We also expect to establish broad principles that may be tested in other neurological conditions that affect bladder function, such as neurodegenerative disorders (e.g. diabetes) and spinal cord injury.
Personalizing Antipsychotic Medicines To Improve Patient Outcomes In Schizophrenia: Development Of Decision Support Tools Using Pharmacometabolomics And Pharmacometrics