Effects Of Muscle Inflammation On Sensory Neuron Excitability
Funder
National Health and Medical Research Council
Funding Amount
$397,398.00
Summary
Muscle pain is a common and poorly treated health problem for many Australians. This project examines the properties of nerves that sense muscle pain and looks at how these change during inflammation, a common cause of muscle pain. We are looking specifically at jaw muscles, which are one of the most common sites of chronic muscle pain. By understanding how muscle nerves are changed by injury, we hope to be able to develop treatments to prevent or reverse these changes.
Professor Lewis is a molecular pharmacologist interested in discovering new venom peptides and ciguatoxins and determining how they interact with the membrane proteins they target using advanced biochemical and spectroscopic methods. Peptides of interest are then modified to improve potency and selectivity. Those with appropriate properties are patented and developed for clinical applications using approaches successfully applied to Xen2174, a conopeptide analogue I co-discovered that is now in ....Professor Lewis is a molecular pharmacologist interested in discovering new venom peptides and ciguatoxins and determining how they interact with the membrane proteins they target using advanced biochemical and spectroscopic methods. Peptides of interest are then modified to improve potency and selectivity. Those with appropriate properties are patented and developed for clinical applications using approaches successfully applied to Xen2174, a conopeptide analogue I co-discovered that is now in Phase II clinical trials for severe pain.Read moreRead less
Regulation Of The Activity And The Surface Expression Of Sodium Channels
Funder
National Health and Medical Research Council
Funding Amount
$466,980.00
Summary
The regulation of transport of salt into and out of the body is essential for the maintenance of blood pressure, and for the maintenance of the correct amount of fluid in the respiratory passages and gut. A critical component of the mechanism by which the body transports salt are sodium channels. Overactivity of these channels leads to increased blood pressure and clogging of the gut and the bronchi due to thick and sticky secretions. Reduced activity leads to abnormally low blood pressure, as w ....The regulation of transport of salt into and out of the body is essential for the maintenance of blood pressure, and for the maintenance of the correct amount of fluid in the respiratory passages and gut. A critical component of the mechanism by which the body transports salt are sodium channels. Overactivity of these channels leads to increased blood pressure and clogging of the gut and the bronchi due to thick and sticky secretions. Reduced activity leads to abnormally low blood pressure, as well as to accumulation of fluid in the lungs such as occurs in influenza and in altitude sickness. The present project will examine the mechanisms by which sodium channels are regulated. It will particularly focus on the mechanisms by which sodium channels are switched off when the salt content of cells is too high.Read moreRead less
Determining The Cellular Mechanisms Involved In The Airway Response To Topical Citrate
Funder
National Health and Medical Research Council
Funding Amount
$444,491.00
Summary
The air passages of the lungs are lined by mucous membranes. These membranes are covered by a thin layer of fluid to protect the airways from drying. This fluid allows the cilia, the hair like projections on top of the airway cells to beat more effectively to remove mucous and inhaled particles from the lungs. The volume and composition of this fluid is determined by the salt and water movement across the mucous membranes of the airways. These processes are abnormal in cystic fibrosis (CF), the ....The air passages of the lungs are lined by mucous membranes. These membranes are covered by a thin layer of fluid to protect the airways from drying. This fluid allows the cilia, the hair like projections on top of the airway cells to beat more effectively to remove mucous and inhaled particles from the lungs. The volume and composition of this fluid is determined by the salt and water movement across the mucous membranes of the airways. These processes are abnormal in cystic fibrosis (CF), the most common lethal inherited disease affecting Australians. In CF, an abnormal gene disrupts one of the major mechanisms for salt and water movement in the air passages. This abnormal salt transport causes drying of the airway surface which impairs the working of the cilia. This leads to retention of mucous in the airways with repeated bacterial infections damaging the lungs. Over the last 10 years, we have developed a series of simple tests to measure the abnormalities in the CF airway of human subjects. We have isolated an exciting new clinical application for sodium citrate, a substance used in blood transfusions. Citrate appears to alter both the salt transport abnormalities found in CF. This research proposal seeks to better understand the dual effects of citrate and to test similar compounds that may have stronger effects. The ultimate aim of our research is to have sufficient knowledge to work out the best way to develop a new treatment for CF.Read moreRead less
EPITHELIAL ION TRANSPORT DEFECTS IN CYSTIC FIBROSIS: PATHOPHYSIOLOGY AND TREATMENT
Funder
National Health and Medical Research Council
Funding Amount
$290,440.00
Summary
The thin layer of fluid covering the surface of the air passages acts to protect the airway surface from drying. This fluid also allows the hair-like projections, or cilia, on the top of the airway cells to beat more effectively. The volume and composition of this fluid is determined by the movement of salt and water across the mucous membranes of the air passages. The importance of this fluid is shown by the problems that occur in Cystic Fibrosis (CF), the most common lethal inherited disease a ....The thin layer of fluid covering the surface of the air passages acts to protect the airway surface from drying. This fluid also allows the hair-like projections, or cilia, on the top of the airway cells to beat more effectively. The volume and composition of this fluid is determined by the movement of salt and water across the mucous membranes of the air passages. The importance of this fluid is shown by the problems that occur in Cystic Fibrosis (CF), the most common lethal inherited disease affecting Australians. In CF, altered salt transport causes drying of the airway surface which impairs the working of the cilia. This leads to retention of mucous in the airway with repeated bacterial infections damaging the lungs. Simple tests have been designed to directly measure the movement of salt across the surface of the nasal passage using a fine soft rubber tube. Movement of mucous in the nose is measured using other simple techniques that are currently used diagnostically. Together, these tests in the nose provide vital information about how the surface of normal human airway moves salt, water and mucous. Any differences found in CF patients will then give us a good idea of the problems found in the CF lung. We will study the interactions between calcium, sodium and chloride in the fluid lining the airways, measuring changes in salt and mucous movement. A range of testing procedures will be used in human volunteers, anaesthetised mice and isolated tissues from sheep. We have already demonstrated important links between the fluid lining the airways and salt movement, and we expect that this may lead to the development of new treatments for Cystic Fibrosis. This therapy will focus on treating the lung problems of CF patients, the major cause of disability. We anticipate that this preventative therapy may offer real benefits in the fight to cure CF.Read moreRead less
Mechanisms Underlying Generation Of Febrile Seizures In Mouse Models Of Human Familial Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$304,559.00
Summary
Febrile Seizures (FS) affect 3% of children aged 0.5 - 6 yrs and have been proposed as an indicator of severe forms of adult generalized epilepsy. Mechanisms underlying FS generation are unknown although studies of Australian families suffering from epilepsy have linked 2 genes to FS. We have generated mice expressing these 2 genes. Aims and Outcomes: to investigate events triggering FS which will provide important insights into why FS occurs in children. (NB: CIA 2 yr career interruption)
Venoms To Drugs: Translating Venom Peptides Into Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$751,854.00
Summary
Chronic pain is a major global health problem that currently affects over three million Australians. There are few drugs available for treating chronic pain and many have significant side-effects. Several ion channels are critical for conducting pain signals to the brain. Blocking these channels can provide pain relief and, in some cases, protection from brain injury following stroke. We are producing potent and selective blockers of these ion channels for the treatment of chronic pain and strok ....Chronic pain is a major global health problem that currently affects over three million Australians. There are few drugs available for treating chronic pain and many have significant side-effects. Several ion channels are critical for conducting pain signals to the brain. Blocking these channels can provide pain relief and, in some cases, protection from brain injury following stroke. We are producing potent and selective blockers of these ion channels for the treatment of chronic pain and stroke.Read moreRead less
Interactions Between Systems That Control Sodium Channels In Renal Epithelia
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The transport of sodium ions by the kidney, gut and lungs not only regulates blood pressure, it also regulates the amount of fluid in the gut and in the lungs. One of the most important proteins that underlie the transport of sodium in these tissues is the so-called epithelial sodium channel. The activity of these epithelial sodium channels is regulated by a wide variety of systems. Some of these regulatory systems act in response to changes in the body's requirements for sodium transport. Other ....The transport of sodium ions by the kidney, gut and lungs not only regulates blood pressure, it also regulates the amount of fluid in the gut and in the lungs. One of the most important proteins that underlie the transport of sodium in these tissues is the so-called epithelial sodium channel. The activity of these epithelial sodium channels is regulated by a wide variety of systems. Some of these regulatory systems act in response to changes in the body's requirements for sodium transport. Others act in response to changes in capacity of cells in which the sodium channels are found to continue transporting sodium. In this project we will study the mechanisms that regulate the activity of the epithelial sodium channels, and in particular, how these mechanisms interact so as to maintain a level of sodium channel activity that is appropriate to both the needs of the organism and to the needs of the sodium transporting cells. The outcomes of this project will be improved understanding of the function of the kidney, gut and lungs in both health and disease. It may also lead to novel drug targets for treatment of major diseases in which the activity of sodium channels is abnormal. These disease include hypertension, cystic fibrosis, pulmonary oedema and influenza.Read moreRead less