Novel Upstream Regulatory And Down-stream Signaling Mechanisms Of The Src-family Protein Kinases
Funder
National Health and Medical Research Council
Funding Amount
$363,639.00
Summary
Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by thei ....Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by their native inhibitor CHK suppresses cancer formation and how over-stimulation of SFKs causes cancer. Exactly how CHK inactivates SFKs remains unclear. Recently, we discovered a novel mechanism employed by CHK to inhibit SFKs. In this mechanism, CHK binds to SFKs tightly and the binding alone is sufficient to completely shut down SFK activity. As this novel inhibitory mechanism of CHK can be exploited for the development of synthetic SFK inhibitors for cancer treatment, we propose to unravel how CHK tightly binds to SFKs and how the binding inhibits the cancer-promoting activity of SFKs. How over-stimulation of SFKs induces the development of human cancer has been an important outstanding question in cancer research. Recently, we and two groups of researchers in Texas achieved breakthroughs in answering this question. The Texan groups discovered that the over-stimulated SFKs cause cancer by shutting down the anti-tumour activity of a tumour suppressor called PTEN. We complemented their findings by discovering how SFKs shut down PTEN activity - SFKs shut down PTEN activity by a chemical modification process called phosphorylation. In this application, we propose to study how SFKs modify PTEN and how phosphorylation shuts down the tumour suppressor activity of PTEN. In summary, our studies will benefit the development of two types of anti-cancer therapeutics: (i) those mimicking CHK binding and inhibition of SFKs, and (ii) those interfering with phosphorylation of PTEN by SFKs.Read moreRead less
Phosphatase Regulators Mediate Long-term Changes In Presynaptic Terminals
Funder
National Health and Medical Research Council
Funding Amount
$984,163.00
Summary
The strength of communication between each nerve cell in the brain depends on how active that nerve cell has been. This enables the brain to be adaptable and is a way for the brain to set up circuits that underlie how we learn and remember. More or less release of chemical messengers (neurotransmitters) into nerve cell junctions changes the strength of nerve cell communication. We have discovered a new chemical signalling pathway controlling neurotransmitter release.
Chemical Aided Phospoproteome Sequencing With Mass Spectrometry
Funder
National Health and Medical Research Council
Funding Amount
$141,000.00
Summary
Essentially all of the body's functions from muscle contraction, energy expenditure through to appetite are controlled by a complex molecular communications system. One of the key elements involves the modification of proteins to alter their properties by adding and removing phosphate. By analysing this process in response to diet and exercise we will obtain a greater understanding of their health benefits and understand how type 2 diabetes and obesity develop at the molecular level.
The Role Of Parasite Adhesins In Plasmodium Falciparum Invasion Of Human Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$385,434.00
Summary
Invasion of red blood cells is essential for the survival of malaria parasite within the human host. Red blood cell invasion is mediated by recognition of parasite proteins to specific blood surface receptors. My research focuses on understanding these parasite protein-host receptor interactions with emphasis on translating these findings as novel approaches for the prevention and treatment of malaria.