Harnessing Tyrosine Metabolism To Combat Respiratory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$866,467.00
Summary
Cross-talk between our immune system and the microbiome is central to health and disease. In particular, the gut microbiome has wide-ranging effects throughout the body, in part through the production of metabolites with immunomodulatory activity. We have discovered a novel subset of microbial metabolites which can protect mice against allergic airway inflammation, a model of asthma. We now aim to discovery how these metabolites work with a view towards developing them as therapeutics.
Presentation Of Metabolite Antigens By MR1 Molecules: A Fundamental System Of Immune Priming
Funder
National Health and Medical Research Council
Funding Amount
$883,832.00
Summary
Our immune system constantly monitors our body for disease-causing microbes, such as bacteria that cause illnesses like pneumonia or tuberculosis. Our cells have a molecular alarm-system called 'MR1' which alerts white blood cells that an infection by microbes is occurring, however this process is not well understood. This grant will allow me to discover the cells and molecular pathways that govern the MR1 alarm system, which may lead to new treatments against common diseases in our community.
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
The body’s normal function depends upon maintaining energy balance matching demand and supply. The body senses its energy status by monitoring metabolite concentrations. I have discovered a metabolite that controls multiple enzymes critical for energy homeostasis and appetite in the body that may provide new approaches to tackle obesity related disease. I have found the metabolite-binding pocket in many proteins and it may represent a major new regulatory network.
The dramatic increase in obesity and age-related metabolic disorders demonstrates the importance of gaining a better understanding of how cells and organisms regulate their energy stores. This project will identify novel molecular mechanisms that control the enzyme CaMKK2, which is a key regulator of whole-body energy metabolism. This will provide new opportunities to inform more effective strategies to tackle metabolic diseases, and improve health in an increasingly ageing population.
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
A Randomised Placebo-controlled Trial Of Antibiotics To Prevent Urinary Tract Infection In Children
Funder
National Health and Medical Research Council
Funding Amount
$735,000.00
Summary
This study is needed to determine whether a common clinical practice long-term antibiotic treatment for children following urinary tract infection (UTI) - is safe and effective in preventing further UTI and if so, whether all appropriate children are being treated. UTI will affect about 10% of Australian children by high school age (88,000 children per year). Because UTI may damage the kidneys, the management priority for children with UTI has been prevention of further infection. Currently this ....This study is needed to determine whether a common clinical practice long-term antibiotic treatment for children following urinary tract infection (UTI) - is safe and effective in preventing further UTI and if so, whether all appropriate children are being treated. UTI will affect about 10% of Australian children by high school age (88,000 children per year). Because UTI may damage the kidneys, the management priority for children with UTI has been prevention of further infection. Currently this means the identification of children thought to be most at risk of recurrent UTI by renal tract imaging. Those found to have reflux of urine from the bladder to the kidney (present in about 30% of those with UTI) are then placed on antibiotics fro 2-5 years. Unfortunately there has never been a properly designed trial to test whether antibiotics do really prevent UTI and if so, whether children with reflux are the appropriate and only group requiring treatment. Long term antibiotics may in fact do more harm than good because of side effects like skin, bowel and blood problems and because resistant bacteria may develop. The design of this study involves the random allocation of placebo or antibiotic (cotrimoxazole, the usual antibiotic given in this case) to about 800 children after their first symptomatic UTI. These children are treated and followed for one year to determine the rate of futher UTI in both groups. Any difference in outcome between the two groups of children will be because of the antibiotic treatment. This study may prove long-term antibiotics are ineffective and therefore should not be routinely used. In this case investigation of children to detect vesicoureteric reflux would serve little purpose and should be abandoned. Alternatively antibiotic treatment may be shown as effective treatment for preventing further UTI and in this case the study will clearly identify those children who will benefit.Read moreRead less
Targeted Pelvic Floor Muscle Training For Urinary Incontinence After Radical Prostatectomy: A Randomised Controlled Trial With Embedded Physiological Studies
Funder
National Health and Medical Research Council
Funding Amount
$966,377.00
Summary
Prostatectomy is a common treatment for the most common cancer in men. Survival is good, but many develop debilitating urinary incontinence. Past pelvic floor muscle training has had limited effect, but recent work has changed understanding of how muscles control continence and compensate for surgery. This clinical trial compares innovative training individually tailored to optimise continence, usual exercise and no treatment, and aims to identify men most likely to benefit from treatment.