The Role Of Force-sensing Ion Channels In Melanoma Migration
Funder
National Health and Medical Research Council
Funding Amount
$553,848.00
Summary
Metastasis of melanoma cells away from the primary tumour site carries a very poor patient prognosis.This research aims to characterise a novel signalling pathway that can regulate the migration (movement) of melanoma cells. This signalling pathway depends on force-sensing platforms that can rapidly convert physical inputs from the environment into an electrical signal within the cell. We are working to understand how these force-sensors function.
The cells that produce and maintain our cartilage, known as chondrocytes, do so by sensing changes in the mechanical environment, but precisely how chondrocytes detect these changes is not known. We are investigating the role of ion channels that are opened in direct response to mechanical movements within the cartilage.This project plans to identify the specific molecules that are participating in this process and to determine if they are therapeutic targets for treatment of osteoarthritis
Structure-function Studies Of Ion Permeation And Selectivity In Recombinant Glycine Receptor Channels
Funder
National Health and Medical Research Council
Funding Amount
$331,300.00
Summary
Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotr ....Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotransmission underlies a range of inherited neurological diseases and already, it has been shown that the human disorder, familial Startle disease (hyperekplexia) occurs because of point mutations that have impaired the permeation and activation of the glycine receptor (GlyR). Similarly, certain epilepsies are now known to be caused by mutations in, or close to, the channel region in the excitatory acetylcholine receptors (AChRs), which affect channel activation and ion permeation. However, because of their very significant structural and functional similarities, information obtained in one member of the LGIC family of receptors has strong potential application to the other members and the GlyR with its simpler structure has certain advantages for investigation. The first aim of this project is to investigate how the molecular biological structure of these ion channels controls permeation, how it affects how different ions are selectively allowed to move through it and how it affects channel activation. A second related aim is to learn more about the process of desensitization of GlyR receptors, whereby a sustained presence of a high concentration of agonist can cause a reduction in receptor response. A third aim is to specifically investigate the mechanisms underlying the mode of molecular disruption resulting from two new Startle disease mutations, which, in addition to their own inherent clinical value, can also give general information about receptor function.Read moreRead less
The Calcium Channel TRPV4 In Skeletal Development And Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$683,069.00
Summary
We have discovered that mutations in a calcium channel gene, TRPV4, cause an inherited osteoarthritis in the hands and feet. This work suggests that TRPV4 may be important in osteoarthritis and suggests the exciting possibility that modulating TRPV4 activity may provide a new therapeutic approach for arthritis. We will study how and why the mutations disrupt channel function and study mouse models to see if they are more or less susceptible to arthritis.
Interaction Of TRP Channels And Inflammatory Mediators: A Critical Role In Visceral Pain
Funder
National Health and Medical Research Council
Funding Amount
$308,747.00
Summary
Transient receptor potential, or TRP channels, are involved in generating many of the sensations we feel, such as touch and pain. The function of these channels can be altered by substances released by the body during inflammation. Some TRP channels have specialized roles in signalling pain from the colon which can be enhanced during colonic inflammation. Understanding how TRP channels and inflammatory mediators function and interact is essential if we are to find treatments for colonic pain.
Neourobiology Of Human Epilepsy: Genes, Cellular Mechanisms,network And Whole Brain
Funder
National Health and Medical Research Council
Funding Amount
$17,652,824.00
Summary
The team is comprised of neurologists, molecular geneticists, physiologists and brain imaging specialists and leads the world in the discovery of the genetic causes of epilepsy. They will continue to identify genes underlying epilepsy and study how genetic variations result in development of seizures. Advanced brain imaging will be used to understand the effects of genetic variation on brain structure and function. This study may lead to new diagnostic methods and treatments for epilepsy.
Determining Fundamental Mechanisms Compromised In Kir-linked Disease States
Funder
National Health and Medical Research Council
Funding Amount
$600,040.00
Summary
The human nervous system and organs are reliant on precisely controlled transmission of electrical currents through sodium and potassium channels. Their core functions are compromised when currents fail to switch on and off normally. Faulty potassium channels are implicated in diabetes, epilepsy and heart failure. This project re-examines the mechanisms controlling potassium channels, with a view to scientific and therapeutic discrimination between the different classes present in human cells.
Modelling TRPV4 Skeletal Disorders Using Human IPSCs
Funder
National Health and Medical Research Council
Funding Amount
$1,171,187.00
Summary
Inherited skeletal disorders are a significant disease burden. Many gene mutations have been defined but we only have limited understanding about how they cause the disease. We will use patient skin cells and new in vitro re-programing technology to induce them to form cartilage cells to produce “disease in a dish” models of human skeletal disorders. These models will allow us to answer questions about how specific mutations cause disease and identify potential therapies
Development Of A New High Throughput Screen For Drug Binding To HERG K+ Channels
Funder
National Health and Medical Research Council
Funding Amount
$351,320.00
Summary
Inadvertent drug block of hERG, a potassium channel in the heart, can cause cardiac arrhythmias and sudden cardiac death. Screening for hERG toxicity has become a major hurdle for development of new drugs. We will use a mutant hERG protein that has enhanced drug binding to develop a high throughput test for hERG toxicity. Identification of dangerous drugs early in the drug discovery process will save the pharmaceutical industry millions of dollars in the costs of brining new drugs to market.
A Novel Therapeutic Target For Preventing Helicobacter Pylori-associated Diseases
Funder
National Health and Medical Research Council
Funding Amount
$750,336.00
Summary
Gastric cancer mainly results from chronic inflammation (gastritis) caused by the stomach-dwelling bacterium, Helicobacter pylori. We have identified a potassium channel which our data suggest could be a new therapeutic target for protecting against gastric cancer caused by H. pylori infection. This project will test the role of this channel in H. pylori gastritis and see whether drugs that target this channel can protect mice against H. pylori-associated disease.