Studies of the pi3-kinase enzyme family using selective inhibitors. The objective of this project is to study the function of the PI3-kinase enzyme family in blood platelets. To do this, inhibitors which block the action of specific family members, will be evaluated for their effects in assays of platelet function. The results will enhance our understanding of the way in which platelets and other cells respond to stimuli, and lead new approaches to designing novel drugs that block these response ....Studies of the pi3-kinase enzyme family using selective inhibitors. The objective of this project is to study the function of the PI3-kinase enzyme family in blood platelets. To do this, inhibitors which block the action of specific family members, will be evaluated for their effects in assays of platelet function. The results will enhance our understanding of the way in which platelets and other cells respond to stimuli, and lead new approaches to designing novel drugs that block these responses.Read moreRead less
Targeted development of dual action antitumour and antiangiogenic agents using differential and functional proteomics. There is an enormous need to develop more effective and less toxic therapeutic approaches to reduce the social and economic burden of cancer. The recent identification of small molecules that can act by both destroying cancer cells and the blood vessels that carry nutrients to them has provided a unique opportunity to define the pathways involved in the action of these agents in ....Targeted development of dual action antitumour and antiangiogenic agents using differential and functional proteomics. There is an enormous need to develop more effective and less toxic therapeutic approaches to reduce the social and economic burden of cancer. The recent identification of small molecules that can act by both destroying cancer cells and the blood vessels that carry nutrients to them has provided a unique opportunity to define the pathways involved in the action of these agents in order to develop more potent drug analogues. Development of these molecules will involve a collaborative and multidisciplinary link with our industry partner and the use of frontier technologies that may lead to improved health and economic outcomes for Australia. Read moreRead less
Covalent Hydrogen Bond Mimetics of Helical Peptide Hormones. Peptide hormones have been identified that adopt a helical shape when bound to their receptor. The project will produce new versions of these hormones by the use of directly bonded chemical linkers in place of the relatively weak helix hydrogen bonds. The resulting hormone mimics will be more stable, have lower molecular weight and be more selective than the natural hormones making them more suitable as drugs. Our new chemical techn ....Covalent Hydrogen Bond Mimetics of Helical Peptide Hormones. Peptide hormones have been identified that adopt a helical shape when bound to their receptor. The project will produce new versions of these hormones by the use of directly bonded chemical linkers in place of the relatively weak helix hydrogen bonds. The resulting hormone mimics will be more stable, have lower molecular weight and be more selective than the natural hormones making them more suitable as drugs. Our new chemical techniques allow us for the first time to fully investigate this approach which if successful will be applicable to many other helical peptides and therefore could be an important drug development technique.Read moreRead less
Inhibition of pro-inflammatory cytokine secretion- A new route to therapeutics of chronic inflammatory disease. Chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease, affect millions of people leading to considerable suffering, economic loss and premature death. Anti-TNF treatments have recently shown success in the treatment of rheumatoid arthritis, inflammatory bowel disease and other conditions, however, a substantial number of patients (~50%) do not re ....Inhibition of pro-inflammatory cytokine secretion- A new route to therapeutics of chronic inflammatory disease. Chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease, affect millions of people leading to considerable suffering, economic loss and premature death. Anti-TNF treatments have recently shown success in the treatment of rheumatoid arthritis, inflammatory bowel disease and other conditions, however, a substantial number of patients (~50%) do not respond to the current TNF treatments. Improved anti-TNF strategies would provide enhanced health outcomes and welcome relief to many Australians. In addition, the economic benefit of the TNF market is very substantial. Therefore the potential impact of this research is very high both for health care and economical potential.Read moreRead less
Novel modes of signalling of serotonin 5-HT2c receptors. This project focuses on a special family of receptor proteins that mediate the actions of the neurochemical, serotonin (5HT), in the human brain. These serotonin receptors are major targets for antidepressant and antipsychotic medications, and also play a role in anxiety, migraine and control of appetite. Despite the important role of serotonin receptors in health and disease, the mechanism of action of many drugs acting on these receptors ....Novel modes of signalling of serotonin 5-HT2c receptors. This project focuses on a special family of receptor proteins that mediate the actions of the neurochemical, serotonin (5HT), in the human brain. These serotonin receptors are major targets for antidepressant and antipsychotic medications, and also play a role in anxiety, migraine and control of appetite. Despite the important role of serotonin receptors in health and disease, the mechanism of action of many drugs acting on these receptors remains unknown. Our project will specifically investigate novel molecular mechanisms associated with serotonin receptor activity that may prove vital in understanding mechanisms of psychiatric illnesses, and how many psychiatric medicines actually work.Read moreRead less
Probing the Tasmanian Devil Serum Proteome for Preclinical Diagnosis of Devil Facial Tumour Disease. The Tasmanian Devil (Sarcophilus harrisii) is a carnivorous marsupial endemic to the island state of Tasmania, and is found all over the state. Over the past decade, a dramatic decline has occurred in the Devil population in association with the emergence of Devil Facial Tumour Disease (DFTD). This project aims to develop a preclinical diagnostic test for DFTD that will provide vital information ....Probing the Tasmanian Devil Serum Proteome for Preclinical Diagnosis of Devil Facial Tumour Disease. The Tasmanian Devil (Sarcophilus harrisii) is a carnivorous marsupial endemic to the island state of Tasmania, and is found all over the state. Over the past decade, a dramatic decline has occurred in the Devil population in association with the emergence of Devil Facial Tumour Disease (DFTD). This project aims to develop a preclinical diagnostic test for DFTD that will provide vital information for use in developing management strategies to ensure the ongoing survival of the Tasmanian Devil. The benefit to Australia in performing this research rests in the new technology that will be developed and the application of this technology to key areas of national and international significance.Read moreRead less
A proteomic approach to identifying the signaling pathway(s) by which acute oxidative stress causes cell death by apoptosis. Oxidative stress following traumatic injury (heart attack or stroke) is known to activate signaling pathways leading to programmed cell death (apoptosis). The aim of this project is to develop methods to identify the signaling proteins involved. Identifying proteins involved in causing cell death will be useful in developing diagnostic tools as well as providing potential ....A proteomic approach to identifying the signaling pathway(s) by which acute oxidative stress causes cell death by apoptosis. Oxidative stress following traumatic injury (heart attack or stroke) is known to activate signaling pathways leading to programmed cell death (apoptosis). The aim of this project is to develop methods to identify the signaling proteins involved. Identifying proteins involved in causing cell death will be useful in developing diagnostic tools as well as providing potential therapeutic possibilities.Read moreRead less
The role of the Ttyh1 protein in cell activation. We have cloned TTYH1, a human homologue of the Drosophila melanogaster tweety gene. The mouse gene has also been identified. The predicted structure of the protein is a membrane protein with 5 transmembrane domains. We have also expressed a GFP-tagged fusion protein in mouse fibroblasts. Confocal microscopy indicates that this protein is likely to be a novel adhesion molecule, with a cellular distribution characteristic of molecules such as integ ....The role of the Ttyh1 protein in cell activation. We have cloned TTYH1, a human homologue of the Drosophila melanogaster tweety gene. The mouse gene has also been identified. The predicted structure of the protein is a membrane protein with 5 transmembrane domains. We have also expressed a GFP-tagged fusion protein in mouse fibroblasts. Confocal microscopy indicates that this protein is likely to be a novel adhesion molecule, with a cellular distribution characteristic of molecules such as integrins. We aim to determine the function of Ttyh1, its interacting intra- and extra-cellular proteins and to assess its candidature as a molecule of importance in cell migration and adhesion.Read moreRead less
Rational structure-based drug design of protein tyrosine kinase inhibitors. Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in diseases such as cancer and immune-related disorders, that cause significant morbidity and mortality within the population. This research proposal aims to develop PTK-specific small molecule inhibitors to combat such diseases. Cytopia's drug discovery capability, coupled with the X-ray crystallographic expertise within Monas ....Rational structure-based drug design of protein tyrosine kinase inhibitors. Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in diseases such as cancer and immune-related disorders, that cause significant morbidity and mortality within the population. This research proposal aims to develop PTK-specific small molecule inhibitors to combat such diseases. Cytopia's drug discovery capability, coupled with the X-ray crystallographic expertise within Monash University, will permit a rational, structure-based drug discovery platform to be established. The ultimate goal of this innovative and mutlidisciplinary approach, namely a portfolio of phase I therapeutics, will be of substantial benefit in the medical health area.Read moreRead less
Determination of the mechanisms of immune system regulation of inflammation by the human protein, chaperonin 10. The aim of this project is to determine the mechanisms by which a human protein, chaperonin 10 (Cpn10), regulates the immune system and suppresses inflammation. When cells of the human immune system are challenged with lipopolysaccharide (LPS) (a product of bacterial infection), the pro-inflammatory cytokine TNF is released. Cpn10 has been shown to suppress production of TNF on chall ....Determination of the mechanisms of immune system regulation of inflammation by the human protein, chaperonin 10. The aim of this project is to determine the mechanisms by which a human protein, chaperonin 10 (Cpn10), regulates the immune system and suppresses inflammation. When cells of the human immune system are challenged with lipopolysaccharide (LPS) (a product of bacterial infection), the pro-inflammatory cytokine TNF is released. Cpn10 has been shown to suppress production of TNF on challenge of cells with LPS, while increasing the levels of the anti-inflammatory cytokine IL-10. Investigating the role of Cpn10 in modulating inflammation will contribute to the understanding and treatment of diseases associated with inflammation, including multiple sclerosis and rheumatoid arthritis.Read moreRead less