Metabolically Reprogramming The Stroma To Starve Pancreatic Tumours
Funder
National Health and Medical Research Council
Funding Amount
$598,848.00
Summary
Pancreatic cancer claims five Australian lives every day. Despite aggressive treatment regimes, there has been no improvement in patient survival in the last decade. Evidence suggests that targeting cancer cells alone is not enough. Pancreatic tumours are surrounded by an extensive scar tissue reaction (stroma). This intense stromal reaction inhibits drug delivery and increases tumour growth. Thus, decreasing the stroma is a potential therapeutic strategy and is the focus of this proposal.
Mechanism Of Anoxic Iron Acquisition In Pathogenic Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$536,280.00
Summary
All organisms require iron for their survival, including all bacterial species. Bacterial pathogens growing in anaerobic environments, such as in our gut, gum, or tissue, sequester iron through the divalent iron transporter FeoB. We aim to divulge the mechanism of iron transport through FeoB by structural and functional studies, and thus provide a scaffold for a non-conventional antimicrobial target.
Many drugs modulate the function of proteins imbedded in cell membranes. Extensive research has been undertaken to better understand drug interactions with these proteins to improve drug therapies, but there has been relatively little progress in understanding the role of the cell membrane. This project will investigate how the cell membrane influences protein function and then use this information to develop novel drugs for the treatment of neurological disorders.
The Structural Basis For Glutamate Transporter Function
Funder
National Health and Medical Research Council
Funding Amount
$373,144.00
Summary
Glutamate transporters are vacuum cleaners in the brain that suck the neurotransmitter glutamate into cells. When the glutamate vacuum breaks down or becomes blocked, glutamate levels outside cells increase, leading to cell death in the brain. This process underlies the damage in many brain diseases including Alzheimer’s disease and stroke. The aim of this project is to understand the mechanism of the glutamate vacuum cleaner so we can develop therapeutics to fix it when it breaks down.
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
Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$551,560.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recre ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recreational drugs (eg. alcohol, nicotine). They are also targets for development of new therapeutic drugs, such as allosteric modulators of nAChR for memory enhancement, or modulating GlyR to relieve spasticity or chronic pain. The project will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, gives rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less
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.