Changes In Pelvic Autonomic Neurons After Spinal Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$176,734.00
Summary
This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic ....This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic autonomic neurons make many new connections between each other, and the types of new connections depend on which spinal nerves have been injured. This leads to the question: are these new connections good or bad? ie are they helpful in trying to get organ control back to normal or will they stop the correct connections from the spinal cord from being made in the future? This project addresses these questions by using sophisticated techniques for staining and visualising individual nerve fibres growing out from the spinal cord. We will track how well these fibres grow back and connect with the pelvic autonomic neurons. In particular, we will see whether they make correct connections, and if these connections are influenced by the new fibres that have grown between the autonomic neurons in the interim period. We will also do physiological tests to see if the new connections have the correct function. The ultimate aim of these studies is not only to understand more about regeneration, but to see what determines whether the correct connections have been made - and ideally, to give us insight into how we can make regeneration work more quickly and accurately. We believe that this work is an important adjunct to other studies on spinal injury, which mostly focuses on regaining voluntary motor control (e.g. walking); however loss of bladder, bowel and reproductive function is another important quality of life issue for spinal injury patients.Read moreRead less
Regeneration Of Pelvic Autonomic Axons After Injury
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
This project is focused on the problem of erectile dysfunction, especially the common situation where this is caused by injury to the penile nerves. These nerves are part of the parasympathetic nervous system . Nerve injury-induced erectile dysfunction is a common problem for prostatectomy patients, with recovery of normal erections occurring slowly, partially or not at all. There is currently no therapy to improve regeneration of these nerves, and this is partly because very little is known abo ....This project is focused on the problem of erectile dysfunction, especially the common situation where this is caused by injury to the penile nerves. These nerves are part of the parasympathetic nervous system . Nerve injury-induced erectile dysfunction is a common problem for prostatectomy patients, with recovery of normal erections occurring slowly, partially or not at all. There is currently no therapy to improve regeneration of these nerves, and this is partly because very little is known about effects of injury on any parasympathetic neurons, and especially for those that are essential for erection. The first aim of this study is to define the key structural and functional changes occurring in penile parasympathetic neurons during regeneration after injury. This fundamental neurobiological knowledge is essential to develop and optimise an future growth treatments. The second aim of the study is to define the effects of a protein, neurturin, on axonal regeneration of penile pro-erectile neurons. Our evidence so far strongly suggests that it is necessary for the early stages of injury responses. Our studies will be performed in mice, where we also have colonies of knockout animals to study the effect of removing neurturin from the regeneration process. Our experiments will include neuroanatomical studies of injured and growing nerves, pharmacology studies on penile smooth muscle (corpus cavernosum) innervation and responsiveness, and tissue culture studies. We will investigate not only the changes that occur following injury to penile nerves, but also the way in which undamaged nerves may assist in returning erectile function.Read moreRead less
Distribution, Pharmacology, Molecular Identity And Roles Of Purine Receptors In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$395,250.00
Summary
Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion an ....Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion and local blood flow. Digestive system diseases, for example irritable bowel syndrome, can involve disordered function of the enteric nervous system, and there is considerable research and development focus to identify drug targets in the enteric nervous system that can be used in therapy. Amongst potential targets are receptors for purines that are located on enteric neurons and are one of the important classes of receptor that is involved in communication between the neurons. These studies aim to identify the purine receptors, their roles in controlling digestive function and their potential as therapeutic targets in the treatment of digestive disease.Read moreRead less
Neurons And Neurotransmitters That Control Phasic Laryngeal Motoneuron Activity
Funder
National Health and Medical Research Council
Funding Amount
$278,736.00
Summary
Opening and closing of the vocal cords with breathing is an automatic function that is present before birth and is essential for life. Opening the vocal cords allows inspired air to enter the lungs and closure serves to protect the lungs from food and drink. Failure of coordination is associated with a range of life-threatening airway disorders, particularly in newborns. Nerves in the brain and the chemicals they release transmit the rhythm of breathing to the nerves that control the vocal cords ....Opening and closing of the vocal cords with breathing is an automatic function that is present before birth and is essential for life. Opening the vocal cords allows inspired air to enter the lungs and closure serves to protect the lungs from food and drink. Failure of coordination is associated with a range of life-threatening airway disorders, particularly in newborns. Nerves in the brain and the chemicals they release transmit the rhythm of breathing to the nerves that control the vocal cords. However, the specific neurons and chemicals involved are not known. This information is crucial in understanding the chemical disorder in the brain responsible for the loss of coordination between breathing and vocal cord activity, and in formulating strategies to treat these conditions using drugs that correct the chemical disorder. By way of example, we have used our animal studies to develop the first ever drug trial to treat children with congenital vocal cord paralysis, whose vocal cords fail to open with inspiration and require a tracheostomy. We have selected a drug that corrects the proposed disorder of brain chemistry responsible for this condition. This approach will serve as a template for the management of a variety of other life-threatening airway disorders in newborns using drugs that act on the brain. We will now carry out further experiments to identify the nerves and their chemicals that control the motoneurons that drive the vocal cords. The key experiment involves recording from inside an individual vocal cord motoneuron in the brain while simultaneously applying a range of chemicals to its external surface. By recording the response of the nerve, we can determine which chemicals control its activity. Using our knowledge of the pattern of chemicals released by respiratory neurons, we will identify neurons for further study, and establish chemical and anatomical relationships between the respiratory nerve and the vocal cord nerve.Read moreRead less
Neurogenic Hypertension In The Spontaneously Hypertensive Mouse : Role Of The Hypothalamic-brainstem Sympathetic Axis
Funder
National Health and Medical Research Council
Funding Amount
$475,917.00
Summary
In human high blood pressure, particularly in the young, an overactive nervous system is thought to be a major underlying cause. Using a unique mouse model of high blood pressure which closely resembles this aspect of the human disease, we will examine which brain cells and neuro- chemicals are involved, particularly in a small area that is involved in regulating the hormonal and nervous system response to stress. From this we hope to be able to target these chemicals with specific therapy.
Exertional Dyspnoea With Increased Filling Pressure - Mechanisms And Treatment Strategies
Funder
National Health and Medical Research Council
Funding Amount
$387,793.00
Summary
Patients with early heart disease often present with shortness of breath with exercise, as myocardial reserve at that stage is usually sufficient to maintain normal function at rest . Indeed, much myocardial dysfunction may originate from the modern lifestyle, including inactivity, obesity, the metabolic syndrome and type II diabetes. The potential benefits of making a definitive early diagnosis are large, because it seems more likely that an impact can be made on the disease process (and theref ....Patients with early heart disease often present with shortness of breath with exercise, as myocardial reserve at that stage is usually sufficient to maintain normal function at rest . Indeed, much myocardial dysfunction may originate from the modern lifestyle, including inactivity, obesity, the metabolic syndrome and type II diabetes. The potential benefits of making a definitive early diagnosis are large, because it seems more likely that an impact can be made on the disease process (and therefore, outcome) than with late stage disease. Current treatment strategies are expensive and because they are directed at end-organ damage (heart failure, heart attacks etc), rather ineffective. This multispecialty, multidisciplinary group will undertake a series of unique studies aimed at identifying early cardiovascular disease. The strategy will involve detection of abnormal filling behaviour at stress echocardiography, with randomization into longterm and short-term trials to examine various therapeutic strategies. Sensitive new cardiovascular imaging techniques will be used to detect preclinical abnormalities in the structure and function of the heart and vasculature, facilitating a mechanistic understanding of the process of increasing filling pressure with exercise.Read moreRead less
Sjogren's Syndrome As A Disorder Of Anti-receptor Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
A new approach to understanding Sjogren's syndrome Sjogren's syndrome (SS) is a frequent cause of illness predominantly in women, leading to frequent attendances to medical, dental and allied health practitioners. Historically considered a rarity, SS, in both its primary and secondary forms, is arguably the commonest manifestation of human systemic autoimmunity. Increasingly recognised by clinicians as the unifying diagnosis underlying a plethora of chronic disabling symptoms in women from the f ....A new approach to understanding Sjogren's syndrome Sjogren's syndrome (SS) is a frequent cause of illness predominantly in women, leading to frequent attendances to medical, dental and allied health practitioners. Historically considered a rarity, SS, in both its primary and secondary forms, is arguably the commonest manifestation of human systemic autoimmunity. Increasingly recognised by clinicians as the unifying diagnosis underlying a plethora of chronic disabling symptoms in women from the fourth decade and beyond, therapeutic options remain limited due to our primitive understanding of its cause. Emerging evidence suggests that rather than a consequence of physical destruction of salivary and tear glands by cells of the immune system, severe dryness of the mouth and eyes in SS might be caused by antibodies which block the transmission of signals from tiny nerves to receptors in these glands. We also have evidence that other symptoms experienced by patients with SS, including abnormal sweating, irritable bladder and bowel, and Raynaud's phenomenon, may also be the consequence of blockage of nerve supply. Furthermore, we have detected these blocking antibodies in patients with both primary SS and rheumatoid arthritis accompanied by secondary SS, pointing for the first time to a common underlying cause for SS in these two settings. We propose a new approach to understanding Sjogren's syndrome, as a disease of anti-receptor autoimmunity, akin to Graves disease of the thyroid gland. This opens up exciting possibilities for the development of new techniques for the diagnosis and treatment of SS.Read moreRead less
Vasomotor Ganglionic Transmission: The Preganglionic Peptide And The Second Gear
Funder
National Health and Medical Research Council
Funding Amount
$451,896.00
Summary
Blood pressure depends on nerve signals that travel from the central nervous system to blood vessels. In the middle of this pathway is a relay station - the sympathetic ganglion cell. Transmission through this relay station has recently been shown to have not only a fixed but also a variable component - the 'second gear'. The project tests if and how three likely candidate peptide molecules, one in the nerves, two in the bloodstream, control this 'second gear' and hence regulate blood pressure.
The Effect Of CPAP On Erectile And Endothelial Dysfunction In Impotent Men With Obstructive Sleep Apnea
Funder
National Health and Medical Research Council
Funding Amount
$609,559.00
Summary
Erectile dysfunction is common in men with obstructive sleep apnea, due to vascular damage, which leads to heart attack. CPAP is the preferred treatment for patients with OSA because of its well-proven ability to decrease sleepiness and improve blood pressure control. This study will establish if CPAP can also improve erectile and vascular endothelial dysfunction. These results will shed light on the mechanisms that underpin the relationship between OSA and Erectile Dysfunction.