Molecular Mechanisms Of Protein Function And Pharmacology In Neuroscience And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$876,005.00
Summary
I have been a Fellow 19 years. It allows me to think strategically on a broader canvass. I am a world authority in endocytosis (how cells interact with the outside world), drug discovery, and protein function, in disciplines of neuroscience and cancer. The outcome will be the first human trials of endocytosis modulators in cancer and epilepsy. Secondly, we will use our new International ProCan Centre to produce a transformational rapid cancer diagnostic and provide new cancer treatment options.
Development Of Small Molecule Isoform-Selective Dynamin Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$85,526.00
Summary
Dynamin has roles in nerve cell communication and in cell division. There are 3 dynamin genes: dynamin I in brain; dynamin II in all cells; and dynamin III in brain and testes. Determination of potential selectivity of small molecule dynamin inhibitors for each dynamin gene can provide a basis for the development of new antiepileptic drugs which are specific for dynamin I and thus neuronal tissues, as well as new anticancer drugs that target dynamin II in nonneuronal cells.
Epilepsy is one of the most common chronic neurological disorders; it affects 1% of the world’s population, yet about 1 in 3 patients fail to achieve seizure control with current drugs. We will improve the properties of small molecules (drugs) that specifically target the GTPase activity of the enzyme dynamin, to reduce seizure effect in the brain by a novel mechanism. We will optimize and pre-clinically test these future chemical entities as potential anti-epileptic drugs.
The Human Immunodeficiency Virus (HIV) is a virus that infects and kills the cells of your immune system. This infection eventually leads to the Acquired Immune Deficiency Syndrome (AIDS). An important aspect in preventing infection is to study how HIV enters immune cells and how infection spreads. Our lab is researching drugs to block the entry of HIV in immune cells, which can hopefully be used together with existing anti-HIV drugs to slow down the spread of the virus and the onset of AIDS.
Defining A Role For The STONED Proteins In The Synaptic Vesicle Cycle
Funder
National Health and Medical Research Council
Funding Amount
$301,527.00
Summary
Nerve cells communicate with each other by means of chemical neurotransmitters. The level of communication is strictly controlled, and changes in the level, either up or down, is known as synaptic plasticity. This plasticity is thought to underly changes in the brain that account for both long and short term memory. Uncontrolled alterations in plasticity can also induce abnormal brain function, resulting in neurological disorders. Changes in the release of neurotransmitter are regulated at the m ....Nerve cells communicate with each other by means of chemical neurotransmitters. The level of communication is strictly controlled, and changes in the level, either up or down, is known as synaptic plasticity. This plasticity is thought to underly changes in the brain that account for both long and short term memory. Uncontrolled alterations in plasticity can also induce abnormal brain function, resulting in neurological disorders. Changes in the release of neurotransmitter are regulated at the molecular level by unknown mechanisms, however the chemical neurotransmitters are enclosed in small vesicles and it is believed that the control of the release of these vesicles, and their recycling, are important components of this mechanism. We have identified a gene that encodes two novel proteins of neurotransmission. Mutations that alter these genes can result in either increased or decreased synaptic activity. By using a combination of genetic and molecular techniques we propose to investigate how one of these two proteins operate to alter synaptic activity, as well as attempting to show how it interacts with other components of the synaptic machinery.Read moreRead less
Dynamin Inhibitors As Tools For Dissecting The Endocytic Pathway In Neurons
Funder
National Health and Medical Research Council
Funding Amount
$470,250.00
Summary
Nerve cells communicate by the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There is a finite number of vesicles, so they are recycled (endocytosis) for reuse. Some human neural diseases hijack the endocytic pathway for entry of pathological peptides, proteins or viruses to paralyse, kill or infect neurons. Our overall aim is to control nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy. At its most ext ....Nerve cells communicate by the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There is a finite number of vesicles, so they are recycled (endocytosis) for reuse. Some human neural diseases hijack the endocytic pathway for entry of pathological peptides, proteins or viruses to paralyse, kill or infect neurons. Our overall aim is to control nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy. At its most extreme, completely blocking endocytosis quickly results in a complete block in nerve communication. Therefore slowing it down (rather than blocking) might be a means to control some neural diseases. For example, a seizure is the uncontrolled firing of neurons. The main mechanisms controlling endocytosis converge on the protein dynamin. Dynamin can assemble into a tiny, tightly wound helix or spring. When energy (GTP hydrolysis) is applied to the nanospring it rapidly releases to cleave off empty recycling synaptic vesicles from the cell wall back into the neuron. Our premise is that blocking the nanospring may lead to a new generation of antiepileptic drugs. To achieve this we have already discovered the first chemical inhibitors of dynamin. In this project we will determine how they work, by showing that they target distinct sites in dynamin. We have embarked on an ambitious chemical synthesis program to greatly improve the potency and specificity of the inhibitors. We will expand this with an iterative approach using combinatorial chemistry. When applied to neurons, the drugs appear to be the first endocytosis inhibitors. Will test our proposal that they will reveal multiple points of action of dynamin in various stages of endocytosis. This project will prove the principle that the development of anti-dynamin drugs could lead to the first anti-endocytic drugs. This has the potential to lead to future development of targeted antiepileptic and anticancer drugs.Read moreRead less
Molecular Mechanisms Of Mitotic Progression And The Anti-cancer Properties Of Anti-mitotic Agents
Funder
National Health and Medical Research Council
Funding Amount
$466,492.00
Summary
Mitosis is the final stage of the cell division cycle that produces two daughter cells. Incorrect localisation and modification of proteins that regulate this process cause cell division errors potentially leading to cancer. This project will characterise how key mitotic proteins co-operatively function to complete this process. This research will increase our understanding of the cell division errors that contribute to cancer development, ultimately identifying new targets for cancer therapy.
Sulfonadyn-based Dynamin I-specific Inhibitors And Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$835,291.00
Summary
Epilepsy affects 1% of people, yet 30% do not respond to anti-epileptic drugs (AEDs). Traditional drug discovery fails to improve this situation. Our team discovered dynamin as a new target for better AED design and our lead sulphonadyns reduces seizures in animals. We will design better sulfonadyns that can ultimately be used for clinical trials by designing the drugs away from its actions outside of neurons. If successful, this will accelerate new AED development with less side-effects.
The Molecular Mechanisms Of Abscission To Complete Cytokinesis
Funder
National Health and Medical Research Council
Funding Amount
$736,337.00
Summary
Cytokinesis is the final stage of cell division that produces two daughter cells. Incorrect localisation and modification of proteins that regulate this process cause cell division errors potentially leading to cancer. This project will characterise how key cytokinesis proteins function co-operatively to complete cytokinesis. This research will increase our understanding of the cell division errors that contribute to cancer development, ultimately identifying new targets for cancer therapy.