Alveolar Macrophage Zinc And Zinc Transporters And Their Role In Phagocytosis
Funder
National Health and Medical Research Council
Funding Amount
$288,975.00
Summary
Zinc is an essential dietary component that serves a number of functions in the lungs. It is both an anti-oxidant and anti-inflammatory agent. Some airway inflammatory diseases such as emphysema may involve a critical loss of lung zinc. We believe that cigarette smoke causes the loss of zinc and this prevents the lung macrophages from working properly to clear bacteria and dead cells. This will provide a foundation for our long term goals of better clinical management of emphysema.
Analysis Of The C-terminal Hypervariable Region Of Ras Proteins
Funder
National Health and Medical Research Council
Funding Amount
$419,241.00
Summary
In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates one major signaling pathway, is mutated in 90% of pancreatic cancers, 50% of colon cancers and 30% of acute leukaemias. This leaves Ras and the signaling pathway permanently switched on causing uncontrolled cell proliferation. The clinical impact of drugs that could neutrali ....In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates one major signaling pathway, is mutated in 90% of pancreatic cancers, 50% of colon cancers and 30% of acute leukaemias. This leaves Ras and the signaling pathway permanently switched on causing uncontrolled cell proliferation. The clinical impact of drugs that could neutralise Ras function in these tumours is potentially enormous. Our previous work demonstrated that Ras must be attached to the inner surface of the cell membrane in order to function properly. This project now seeks to understand exactly how Ras gets to and attaches to the cell membrane. Once we understand this mechanism drugs can be designed to block Ras getting to the membrane. Such drugs should neutralize the effect of Ras in tumours and control cell proliferation. In fact, our previous study has already led to the identification of the first generation of anti-Ras drugs that work on this principle.Read moreRead less
Role For Zinc And ZIP2 In The Action Of Nitric Oxide And In Vascular Protection Against Cigarette Smoke And Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$685,941.00
Summary
The NO/cGMP signalling pathway, which is central to cardiovascular physiology and protection against disease, is only fully effective when there are adequate levels of zinc in the vascular endothelium. This is especially important where zinc stores are depleted (elderly, smokers, diabetics and kidney disease). There is an urgent clinical need to implement strategies to monitor vascular Zn status. This application will explore the underlying science and translate these to the clinic.
Role Of Zinc In The Respiratory Epithelium And Asthma
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a significant proportion of the Australian community. For example ....This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a significant proportion of the Australian community. For example, asthma affects 12% of adults and amongst these, 15% waken weekly or more often with their asthma while 6% are hospitalized annually. There is a need to understand the basic mechanisms underlying these diseases so that new strategies can be developed to modify bronchocondtriction and inflammation. The project will provide new knowledge concerning the physiology of Zn in the respiratory epithelium and interactions between Zn deficiency and oxidants on injury in the respiratory tract. The usefulness of easily accessible nasal epithelial cells as a measure of Zn and Zn transporter levels deeper in the respiratory tract will be assessed. The project encompasses a number of fields and utilizes in vitro cellular and animal models, as well as tissues from human subjects.Read moreRead less
Defining The Role Of Zinc At The Host-pneumococcal Interface
Funder
National Health and Medical Research Council
Funding Amount
$870,925.00
Summary
Streptococcus pneumoniae is the world’s foremost bacterial pathogen. In Australia, bacterial infections are responsible for more than 9000 deaths every year, and the economic burden associated with treating diseases arising from pneumococcal infections is more than $1 billion annually. This proposal aims to define the role of the transition metal zinc in innate immune resistance to bacterial infection. This knowledge will reveal new targets for next generation antimicrobial therapeutics.
Huntington’s disease is a devastating neurological disorder, with no drugs currently available to cure or treat the underlying cause. Our recent laboratory work on a drug called PBT2 was the foundation of a encouraging clinical trail for this disease. Here, we propose to investigate a drug called Zn(DTSM) for this disease, which has similar properties to PBT2, but we expect will have a greater effect.
Characterization Of 72 And 52 KDa Inositol Polyphosphate 5-phosphatases: Role In Vesicular Trafficking And Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
Cells respond to the external environment, stress, hormones and grow th factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes or kinases that modify these membrane lipids in particular an enzyme known as the PI 3-kinase generate potent signalling molecules that regulate cell growth. It has been shown by many studies that signals generated by ....Cells respond to the external environment, stress, hormones and grow th factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes or kinases that modify these membrane lipids in particular an enzyme known as the PI 3-kinase generate potent signalling molecules that regulate cell growth. It has been shown by many studies that signals generated by the PI 3-kinase are amplified in certain human cancers. Inherited cancer syndromes have been described in which the cell has lost the ability to switch off these lipid messenger molecules. The current project aims to investigate two recently identified enzymes called 5-phosphases that have the ability to terminate PI 3-kinase membrane signals. Both these enzymes were isolated and characterized by the host laboratory and it is predicted they will play distinct roles in the cell. The 72 kDa 5-phosphatase is predicted to regulate protein and vesicular trafficking to the surface of cell. This proposal aims to investigate if the 72 kDa 5-phosphatase can regulate the intracellular sorting of new proteins within the cell. We have also noted the 72 kDa 5-phosphatase may play a role in the development of the nervous system in particular the ability of nerves to send branches out and differentiate. This proposal will investigate this hypothesis. The second enzyme that we have isolated is a 52 kDa 5-phosphatase. This enzyme is present in many cells. We have compelling evidence that the enzyme forms a complex with a recently decribed protein called SODD that stops cells from dying in response to inappropropirate signals. We predict the 52 kDa 5-phosphatase may function to prevent prolonged cell survival as is observed in cancer. We will investigate if this enzyme regulates the cell death pathway and if increased or decreased levels of the 52 kDa 5-phosphatase alter cell survivalRead moreRead less
Development Of Novel Anti-epileptic Drugs Targeting Vesicular Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$202,950.00
Summary
Our team developed a drug program targeting a novel mechanism for epilepsy treatment, neuronal synaptic vesicle endocytosis. This project will develop the most promising series of drugs. Preclinical development is advanced, lacking only efficacy data across models predictive of the spectrum of human epilepsies to enable candidate selection for clinical trials. The program will advance a totally new concept for the treatment of epilepsy.