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
Our studies are aimed at examining how blood flow and pressure is controlled in the various tissues of the body. In particular, we hope to improve our understanding of how blood flow is matched to local metabolic requirements and how a constancy of conditions can be maintained despite changes in overall blood pressure. This ability to control local blood flow occurs through the ability of very small arteries to rapidly adjust their diameters through vasoconstriction or vasodilatation. The vessel ....Our studies are aimed at examining how blood flow and pressure is controlled in the various tissues of the body. In particular, we hope to improve our understanding of how blood flow is matched to local metabolic requirements and how a constancy of conditions can be maintained despite changes in overall blood pressure. This ability to control local blood flow occurs through the ability of very small arteries to rapidly adjust their diameters through vasoconstriction or vasodilatation. The vessels can thus act as valves regulating the transfer of blood flow and pressure to smaller vessels downstream. One particular response that small arteries exhibit is the ability to constrict when pressure within the vessels increases. The increase in pressure appears to stretch the vessel wall which in turn initiates a series of mechanical and biochemical steps that ultimately lead to contraction of muscle cells within the vessel wall. By contracting, the vessels limit the increase in downstream flow and pressure that would be expected to occur. The vessels being studied are very small, typically less than 100 micron. They are studied under isolated and controlled conditions using microscope and computer-based imaging techniques. While this allows us to directly monitor changes in vessel diameter to various stimuli (e.g. a change in pressure) we have also had to miniaturize biochemical measurements so we can understand the chemistry which underlies these vasoconstrictor responses. Understanding of how these local blood regulatory mechanisms occur is not only relevant to our understanding of the normal situation but is also vital to understanding disease states. For example, this work is very relevant to common cardiovascular disorders such as hypertension. It is hoped that a detailed understanding of the biochemical pathways by which small arteries contract will allow the design and targeting of pharmaceutical approaches for treatment of vascular disease states.Read moreRead less
The Role Of Na-Ca Exchange Current In Cardiac Pacemaker Cells
Funder
National Health and Medical Research Council
Funding Amount
$263,100.00
Summary
The heart rate is controlled by a small group of pacemaker cells within the heart. The pacemaker cells fire spontaneously and this intrinsic rate is modified by the sympathetic and parasympathetic nerves of the autonomic nervous system. We are studying a new current in the pacemaker cells which helps to control the firing rate. This new current is controlled by the intracellular calcium inside the cells so we are also studying the way in which intracellular calcium changes when the autonomic ner ....The heart rate is controlled by a small group of pacemaker cells within the heart. The pacemaker cells fire spontaneously and this intrinsic rate is modified by the sympathetic and parasympathetic nerves of the autonomic nervous system. We are studying a new current in the pacemaker cells which helps to control the firing rate. This new current is controlled by the intracellular calcium inside the cells so we are also studying the way in which intracellular calcium changes when the autonomic nervous system is active. This project will provide new insights into the function of this small group of critical cells and may allow treatment of some cardiac arrhythmias without the expense and surgery involved in the use of artificial pacemakers.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
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.
Physiological Function Of Nedd4-2 In Regulating The Epithelial Sodium Channel And Cystic Fibrosis Transmembrane Conductance Regulator
Funder
National Health and Medical Research Council
Funding Amount
$949,572.00
Summary
Optimal transport of sodium and chloride ions is essential for the maintenance of electrolyte balance, blood volume, blood pressure and lung function. We are studying the control of a key sodium channel (the epithelial sodium channel) and a key chloride channel (cystic fibrosis transmembrane conductance regulator) by an enzyme called Nedd4-2. This project will enable us to understand how Nedd4-2 regulates these two ion channels and to study the pathological consequences of the loss of Nedd4-2.