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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
Investigations Of Mechanisms Underlying Autonomic Cardiovascular Regulation In Medial Temporal Lobe Epilepsy.
Funder
National Health and Medical Research Council
Funding Amount
$311,860.00
Summary
People with epilepsy often show disturbed cardiovascular function which may increase mortality risk. This may reflect seizure related disturbances in the autonomic circuitry regulation of the cardiovascular system. We apply advanced brain imaging analysis of altered neural structure, circuit connectivity and function within medial temporal lobe and mid brain, combined with clinical assessment of autonomic function to provide important new insights into cardiac disturbances in epilepsy.
A novel sensory neural circuit has been identified innervating the airways and lungs. The anatomical organisation of this circuit has been described to some extent in previous studies, however there is a significant gap in knowledge with respect to its functional importance. This project will develop methods to address this knowledge gap and in doing so the project will firstly describe how this circuit controls breathing under normal conditions and secondly how this becomes dysregulated during
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
Molecular And Cellular Studies Of The Adaptive Immune Response In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$16,509,154.00
Summary
Immune responses protect us against pathogens such as viruses and bacteria. However inappropriate immune responses can result in autoimmune conditions such as systemic lupus erythmatosus, multiple sclerosis, type I diabetes, asthma as well as immunodeficiencies. The aim of our proposal is to gain a thorough understanding of how all the cells of the immune system function and interact with each other, and what goes wrong when inflammatory diseases develop. We plan to do this using state-of-of-the ....Immune responses protect us against pathogens such as viruses and bacteria. However inappropriate immune responses can result in autoimmune conditions such as systemic lupus erythmatosus, multiple sclerosis, type I diabetes, asthma as well as immunodeficiencies. The aim of our proposal is to gain a thorough understanding of how all the cells of the immune system function and interact with each other, and what goes wrong when inflammatory diseases develop. We plan to do this using state-of-of-the-art technologies, including genetically modified mice, gene microarrays, monoclonal antibodies, and flow cytometry. We have brought together Australia's leading immunologists with complimentary expertise and research interests in specific areas of immunology including cytokines, cell migration, inflammatory diseases, autoimmunity and cell-cell interactions. One aspect of the application is to understand the genetic and molecular basis of immunological diseases. However we also wish to move on from an understanding to treatment of immunological diseases through the development of novel therapeutics. We will form collaborations with biotech and pharmaceutical companies (including our own spin off companies) to advance important new therapeutics for autoimmune and allergic diseases. These conditions represent a significant health burden to Australia.Read moreRead less
How Does Chronic Epilepsy Result In Cardiac Electrophysiological Dysfunction?
Funder
National Health and Medical Research Council
Funding Amount
$737,112.00
Summary
Cardiac dysfunction is common in epilepsy, and could be an important contributor to the increased risk of sudden death in people with epilepsy (SUDEP). In this grant we will investigate: when changes in the cardiac function develop in relation to the epilepsy; if people with chronic epilepsy have similar changes; and what effect seizures and epilepsy has on the nerves innervating the heart. The outcomes have the potential to motivate new treatments and prevention for this important problem.
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
Unravelling The Neuropathological Basis Of The Gastrointestinal Manifestations Of Parkinson’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$822,957.00
Summary
Parkinson’s Disease occurs in about 1% of the population. It is a distressing, progressive disease that places a severe burden on patients, families and carers. 80-90% of Parkinson’s Disease patients have constipation which causes substantial distress to patients, their families and carers. We have a rational path to therapy for constipation of Parkinson’s Disease that will be pursued in this project