I am a lab-based neurochemist-cell biologist with expertise in protein chemistry and pharmacology. My research focuses on the dynamin family of proteins in the endocytosis of synaptic vesicles and in the molecular mechanisms of synaptic transmission in th
Mechanisms Of Synaptic Vesicle Endocytosis Revealed By Its Regulatory Phosphoproteome
Funder
National Health and Medical Research Council
Funding Amount
$545,216.00
Summary
The nerve cells in our brains are in constant communication to sustain life. Communication involves electrical stimulation of one nerve cell which then responds by releasing chemical messengers, from vesicles, onto the next cell. Our research focuses on the mechanism of recycling of vesicles. Targeting this mechanism is a way to gain fundamental knowledge of how to intervene medically when communication fails, or when communication needs to be dampened, such as in some neurological diseases.
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
Functional Characterisation Of A New Regulatory Mechanism For CaMKII At Synapses In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$547,315.00
Summary
CaMKII is an important regulatory molecule in the brain where it plays an essential role in certain forms of learning and memory and in the appropriate development and maturation of neural pathways and undergoes specific changes in animal models of brain ischaemia and epilepsy. Recent evidence has shown that, in nerve cells, the regulation and role of CaMKII is more complicated than previously thought. This project will investigate the roles of a new control mechanism in regulating the function ....CaMKII is an important regulatory molecule in the brain where it plays an essential role in certain forms of learning and memory and in the appropriate development and maturation of neural pathways and undergoes specific changes in animal models of brain ischaemia and epilepsy. Recent evidence has shown that, in nerve cells, the regulation and role of CaMKII is more complicated than previously thought. This project will investigate the roles of a new control mechanism in regulating the function of CaMKII in nerve cells. The experiments will involve an international team of collaborators using cutting edge techniques at the molecular, cellular and whole animal level. This will provide a more complete understanding of how CaMKII influences brain function and allow an assessment of whether CaMKII regulation might be a suitable target for drugs aimed at protecting against the damaging effects of brain injury following stroke or heart attack.Read moreRead less