PROBABILITY OF QUANTAL SECRETION AT NEUROMUSCULAR SYNAPSES
Funder
National Health and Medical Research Council
Funding Amount
$334,232.00
Summary
The classical preparation for the study of synaptic transmission is the amphibian neuromuscular junction, for which there is the largest body of experimental data. This synapse was instrumental in the discovery that transmitters are released in packets or quanta, that this occurs at specialized release sites in the nerve terminal, and that receptor molecules on the muscles cells are strategically placed to receive the transmitter. Our work on this synapse has shown that each of these release sit ....The classical preparation for the study of synaptic transmission is the amphibian neuromuscular junction, for which there is the largest body of experimental data. This synapse was instrumental in the discovery that transmitters are released in packets or quanta, that this occurs at specialized release sites in the nerve terminal, and that receptor molecules on the muscles cells are strategically placed to receive the transmitter. Our work on this synapse has shown that each of these release sites have different probabilities for the secretion of a quantum and that this probability is correlated with the width of the release site. More recently we have shown that, whilst the size of a quantum does not vary between adjacent release sites, the area over which the quantum is released does vary between sites. The probability of quantal secretion is proportional to this area, as is the number of vesicles present at the release site. In this project we intend to relate this probability of secretion to the proteins that regulate the release of a quantum and in particular how these proteins interact to determine the time course of increase in probability at a release site after the passage of an impulse. The affects of trains of impulses on this probability are also to be delineated, in particular how the calcium which enters the terminal during these trains determines a long-term enhancement in probability after the train has ceased. This research will provide a molecular description of secretion from motor-nerve terminals.Read moreRead less
The corticospinal pathway is the major route from the brain to the spinal cord for the control of voluntary movement in people. Little is known about how transmission through this pathway might alter with activity. It is known that, elsewhere in the brain, connections between nerve cells can be made stronger or weaker by specific patterns of activity and it is thought that such changes underlie learning and memory. We propose that similar changes might happen in the spinal cord at the connection ....The corticospinal pathway is the major route from the brain to the spinal cord for the control of voluntary movement in people. Little is known about how transmission through this pathway might alter with activity. It is known that, elsewhere in the brain, connections between nerve cells can be made stronger or weaker by specific patterns of activity and it is thought that such changes underlie learning and memory. We propose that similar changes might happen in the spinal cord at the connection between the nerve cells which carry signals from the brain and the nerve cells which carry the signals out to the muscle. This project will demonstrate that the connections in the pathway from the brain to the muscle can be strengthened or weakened in a controlled way by imposed patterns of activity. In addition, we know that after voluntary contractions, there are dramatic changes in the way signals in this pathway are transmitted to muscles. After brief strong voluntary contractions, muscle responses are immediately reduced. After longer contractions in which the muscles become fatigued, the reduction is followed by an increase in responses which can last many minutes. Thus, this project will also study changes in the pathway from the brain to the muscle after natural activity. The effects of changes induced by artificial or natural activity on the control of voluntary movement will also be investigated. Understanding how activity drives changes in the pathway that controls voluntary movement is important for all situations that involve learning motor tasks. These include normal development and learning of motor skills, as well as rehabilitation after all kinds of nerve or muscle injury. It is also important in understanding motor changes that occur when activity is altered by disorders like spinal cord injury or stroke. Improved understanding of the processes occuring should allow improvement in rehabilitation therapies.Read moreRead less
How Changes In The Motor Cortex And Spinal Cord With Exercise Contribute To Fatigue In Humans
Funder
National Health and Medical Research Council
Funding Amount
$311,250.00
Summary
Fatigue with exercise is a common experience in healthy people and can be a problem in many illnesses. With fatigue people are less able to produce force with their muscles. Much of this weakness occurs because of events in the muscles but some results from changes in the nervous system. The size of the contribution of the nervous system to fatigue is not known for the kinds of exercise that cause fatigue in everyday life e.g. prolonged weak contractions like holding the shopping or a plate of f ....Fatigue with exercise is a common experience in healthy people and can be a problem in many illnesses. With fatigue people are less able to produce force with their muscles. Much of this weakness occurs because of events in the muscles but some results from changes in the nervous system. The size of the contribution of the nervous system to fatigue is not known for the kinds of exercise that cause fatigue in everyday life e.g. prolonged weak contractions like holding the shopping or a plate of food, rhythmic contractions like walking or painting a wall, and more vigorous exercise that causes changes in breathing and body temperature. The behaviour of nerve cells in the brain and spinal cord is altered in fatigue but how and why many of these changes occur, and how they affect the control of movements, is poorly understood. Three approaches are planned. In the first set of studies, we will use brain and nerve stimulation to measure the impact of sustained low-level activities on people's ability to drive their muscles fully. We will identify whether such activities, as well as increased demands on other body systems, can cause fatigue in the nervous system. In the second set of studies, we will investigate whether changes in the motor areas of the brain can alter peoples' performance of fatiguing motor tasks or their perception of how much effort the tasks take. Finally, we will use stimulation of the spinal cord to work out why motor nerve cells in the spinal cord fire more slowly with fatigue. Fatigue is an important symptom which is not confined to diseases of any one system in the body. For example, it is a major complaint in multiple sclerosis, cardiac failure, chronic obstructive airway disease, depression and cancer, as well as after chemotherapy, surgery, and viral illness. The implications of better understanding of the contribution of the nervous system to fatigue range from targeting treatments in patients to improving the performance of athletes.Read moreRead less
Economic, social and cross cultural issues in non-pharmaceutical protection of front line responders to pandemic influenza and emerging infections. The protection of front line responders in a pandemic is essential to underpin an effective response. This research is the only work internationally which will address a key gap in evidence. This research has major implications for the national stockpile and for management of front line responders in a pandemic. These data are urgently needed, not ju ....Economic, social and cross cultural issues in non-pharmaceutical protection of front line responders to pandemic influenza and emerging infections. The protection of front line responders in a pandemic is essential to underpin an effective response. This research is the only work internationally which will address a key gap in evidence. This research has major implications for the national stockpile and for management of front line responders in a pandemic. These data are urgently needed, not just in Australia, but globally to inform pandemic planning and disease control policy around emerging infections and bioterrorism.Read moreRead less
THE EFFECT OF LONG ACTING BRONCHODILATORS ON VENTILATION IN COPD
Funder
National Health and Medical Research Council
Funding Amount
$143,676.00
Summary
COPD is a common and important smoking-related lung disease. Well-established treatments with inhaled medications including long-acting bronchodilators have a proven clinical track record. However the physiological basis for their effects is still under investigation. This research examines some of the physiological changes in lung function and the response to long-acting bronchodilators in patients with COPD, and may help explain why some patients respond to therapy while others do not, leading ....COPD is a common and important smoking-related lung disease. Well-established treatments with inhaled medications including long-acting bronchodilators have a proven clinical track record. However the physiological basis for their effects is still under investigation. This research examines some of the physiological changes in lung function and the response to long-acting bronchodilators in patients with COPD, and may help explain why some patients respond to therapy while others do not, leading to more targeted therapeuticsRead moreRead less
Resolving Eosinophil And Inflammatory Heterogeneity In Chronic Allergic Airway Disease For Safer, Effective And Lasting Precision Therapies
Funder
National Health and Medical Research Council
Funding Amount
$1,166,165.00
Summary
Many patients with upper airway inflammation and asthma have poorly controlled disease and are in need of new effective therapies. We have discovered new cell subsets in the airways of these patients. We will use cutting edge single cell and spatial analysis of human tissues to define human allergic disease and inflammatory cells at unprecedented resolution. This will identify new targets for treatment and match patients with effective therapies to facilitate precision therapy.
Making Signalling Through The Tumour Necrosis Factor Receptors Selective For Promoting Neutrophil Antimicrobial Activity
Funder
National Health and Medical Research Council
Funding Amount
$196,312.00
Summary
It is evident to the professional and general community that antibiotic and drug resistance displayed by bacteria is a continuing and growing problem in the treatment of infection with potentially casastrophic effect on the health of our community. This concern is only partly reduced by our potential to develop new antimicrobial agents and vaccines. If we were able to use immunomodulators in a relatively safe and appropriate manner to target and enhance the antimicrobial power of specific compon ....It is evident to the professional and general community that antibiotic and drug resistance displayed by bacteria is a continuing and growing problem in the treatment of infection with potentially casastrophic effect on the health of our community. This concern is only partly reduced by our potential to develop new antimicrobial agents and vaccines. If we were able to use immunomodulators in a relatively safe and appropriate manner to target and enhance the antimicrobial power of specific components of the immune system then this could be exploited in the treatment of infection. While body proteins formed (cytokines) which modify the behaviour of the immune system are being used as pharmaceuticals, their toxic side effects are problematic to the patient. Our project focusses on one of the cytokines, tumor necrosis factor (TNF), which increases the antimicrobial activity of phagocytic cells but in addition can have quite devastating effects on other tissues in the body. This is because when TNF binds to its receptor on cells and tissues it elicits a multitude of signals inside the cell which can also precipitate illness. The purpose of our investigations is to identify which signals are responsible for increasing resistance against infection and which are not. With this information we will then see if it is feasible to selectively stimulate this signal from outside the cell since this has a better chance of succeeding as a pharmaceutical. This task is likely to be achievable since our research team has made some unique observations about TNF signalling characteristics and we have developed a peptide TNF mimetic which shows only the characteristics of increasing antimicrobial activity.Read moreRead less