Zbtb11 is a druggable protein that is mis-expressed in blood cancers - second biggest cause of cancer death in Australia - and liver cancer, third leading cause of death from cancer worldwide. We have found that it interacts with 2 other proteins with potential roles in these diseases. Our studies examine the nature of these Zbtb11-partner interactions and their particular consequences for blood disorders. Zbtb11 contributions to disease development will be a target for novel disease therapy.
Investigation Of A New Rheology Dependent Platelet Aggregation Mechanism
Funder
National Health and Medical Research Council
Funding Amount
$509,447.00
Summary
We plan to examine a new mechanism promoting blood clot formation that involves the clumping (aggregation) of blood platelets. Our central hypothesis is that disturbances of blood flow, as occurs in diseased arteries, activates this clotting mechanism through a unique platelet activation process. Defining this new activation mechanism has the potential to lead to new approaches to prevent blood clot formation in patients with heart disease.
Klf5 Function In Normal And Leukaemic Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$609,924.00
Summary
Acute Myeloid Leukaemia (AML) is a devastating disease that affects both children and adults. New treatments that target particular genetic abnormalities are urgently needed. We have identified KLF5 as a gene that may control blood cell maturation. In AML patient samples we have found alterations of the KLF5 gene that may suppress its activity and contribute to the formation of leukaemia. These leukaemias may be good candidates for treatment with new drugs called methyltransferase inhibitors.
Investigate The Role Of PAF And CD40 Ligand In Regulating The Proinflammatory Properties Of Platelets
Funder
National Health and Medical Research Council
Funding Amount
$507,270.00
Summary
The cells of the blood play an important role in maintaining healthy blood vessels. We are interested in two types of blood cells, platelets and leukocytes, which together play a key role in vessel maintenance, by promoting blood clot formation and vessel wall repair following injury. However, while critical for normal blood vessel maintenance, these cells have also been demonstrated to contribute to disease states including atherosclerosis, thrombosis and inflammatory airway diseases. Underlyin ....The cells of the blood play an important role in maintaining healthy blood vessels. We are interested in two types of blood cells, platelets and leukocytes, which together play a key role in vessel maintenance, by promoting blood clot formation and vessel wall repair following injury. However, while critical for normal blood vessel maintenance, these cells have also been demonstrated to contribute to disease states including atherosclerosis, thrombosis and inflammatory airway diseases. Underlying the function of both blood cell types is their ability to stick (or adhere) to each other. However the way in which they coordinate this adhesion is very complex. New information from our laboratory has demonstrated that the sticky behaviour of each cell type is spatially and temporally regulated, and may involve may factors both inside and outside of the cells themselves. Our studies aim to define the key components regulating the 'stickiness' of these blood cells, in order to undertand how they contribute to maintaining healthy vessel walls, but also how their stickiness may also contribute to the promotion of diseased vessels. This information will not only increase our knowledge of the factors that regulate blood clot formation, but may also assist in the development of new therapies to prevent and-or treat vessel disease.Read moreRead less
Modern chemotherapies are designed to exert maximal effect on tumour cells while having minimal side-effects on normal cells. Remarkable advances in our understanding of the molecular biology of cancer has provided possible avenues for more successful targeted cancer treatments. Several crucial interactions between cancer-specific proteins called oncoproteins , occur largely in tumour cells and thus provide ideal targets for intervention. The proposed project is to develop a model system for a t ....Modern chemotherapies are designed to exert maximal effect on tumour cells while having minimal side-effects on normal cells. Remarkable advances in our understanding of the molecular biology of cancer has provided possible avenues for more successful targeted cancer treatments. Several crucial interactions between cancer-specific proteins called oncoproteins , occur largely in tumour cells and thus provide ideal targets for intervention. The proposed project is to develop a model system for a target specific therapy of leukaemia cells by blocking the interactions between oncoproteins. Moreover, the ability to isolate specific blockers of particular protein-protein interactions provides an opportunity to unravel complex genetic pathways in mammalian systems, which are relatively intractable by other analyses. The dissection of pathways using specific blockers may also provide a useful avenue for identifying new drug targets. We have chosen to target particular interactions involving one known oncoprotein in the search for specific inhibitors. A genetic selection will be used to identify random, constrained peptide sequences which are capable of blocking these interactions and which do not interfere with other interactions involving the oncoprotein. This technique allows one to select for or against specific blockers of known interactions from a library containing millions of candidate drug leads in baker's yeast cells. This procedure will be most suitable for high through-put drug screening projects. The validity of this approach to the identification of new peptide drug leads will be finally established in vivo using transgenic models of oncoprotein-dependent cancer in mice.Read moreRead less
Dissecting The Role Of The IL-3 Receptor Alpha Subunit And Beta-catenin In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
Leukaemia is a devastating form of blood cancer affecting both young and old. We aim to understand the mechanisms of uncontrolled cell growth associated with acute myeloid leukaemia. We focus on the role of key growth regulators that are abnormally active in the critical leukaemia stem cells. Understanding the biological and molecular properties of these cells is of considerable importance for development of the next generation of leukaemia therapies.
Dissecting FLT3 Signalling In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$498,328.00
Summary
Each year approximately 6000 Australian adults and children are diagnosed with leukaemia, lymphoma or a related blood disorder, accounting for about 15% of all cancers. Acute Myeloid Leukaemia (AML) is the most common form of leukaemia in adults resulting from an accumulation of immature myeloid cells in the bone marrow and peripheral blood as a result of sustained, abnormal cell growth and survival together with a block in normal blood cell formation. There is still a major research effort aime ....Each year approximately 6000 Australian adults and children are diagnosed with leukaemia, lymphoma or a related blood disorder, accounting for about 15% of all cancers. Acute Myeloid Leukaemia (AML) is the most common form of leukaemia in adults resulting from an accumulation of immature myeloid cells in the bone marrow and peripheral blood as a result of sustained, abnormal cell growth and survival together with a block in normal blood cell formation. There is still a major research effort aimed at understanding the mechanisms that lead to AML formation and it is clear that multiple AML oncogenes and tumour suppressors remain to be identified. Identification of further events involved in AML is important as it will provide avenues for more specific and less toxic treatments. These are needed because current success rates for AML remain relatively poor. It is critical that research into the understanding of the pathways and events involved in AML keeps pace with the rapid development of new approaches for therapeutic agents. Together this will greatly increase the scope for therapeutic intervention over the next decade. In this application we investigate the role of a new molecular pathway in AML. Our studies have identified a gene of particular interest that we propose normally prevents AML formation and therefore is frequently turned off by the cellular changes that lead to AML. We propose that silencing of this gene is particularly important in those AML cases which have mutations in the cell surface receptor FLT3 (about 30% of AML cases). We will use a number of molecular and cell biology approaches to manipulate this gene in mouse cell lines, normal mouse cells and human AML cells. A better understanding of the role of this gene and the associated pathway involving FLT3 may generate new leads for therapeutic approaches.Read moreRead less
The Role Of Med12, A Subunit Of RNA Polymerase II Mediator, In Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$495,490.00
Summary
In a screen of zebrafish for mutations in blood cell development, we isolated a mutant called syrah. The mutation causing the blood defect was identified in a gene called med12, which encodes a component of the RNA transcription machinery in cells. To understand how this mutation causes a reduction in blood cells, we will identify the proteins that interact with the med12 protein. Understanding the pathway involved may lead to the discovery of new causes of human congenital blood diseases.
Platelet Receptor Regulation In Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$507,536.00
Summary
In response to bleeding, blood platelets use receptors to form a thrombus (blood clot) and block further loss of blood and aid tissue repair. People treated with heparin prior to surgery, can form autoantibodies that attack platelets, leading to thombus and thrombocytopenia (dangerous loss of circulating platelets). This is a significant clinical problem that is difficult to diagnose. We will determine how platelet receptor shedding can aid the diagnosis of heparin-induced thrombocytopenia.
Use Of Retroviral Expression Libraries To Characterise Mechanisms Of Drug Resistance In Leukaemia.
Funder
National Health and Medical Research Council
Funding Amount
$362,545.00
Summary
At present, treatment of leukaemia is based either on established chemotherapeutic drug treatment or newly identified inhibitor drugs currently being tested as part of clinical trials. Both these treatments are known to induce or select for resistance to the drugs in some cases. Resistance usually reduces the success rate of any further treatment with the same or similar drugs. To discover possible ways of overcoming drug resistance it is important to understand the mechanisms that are responsib ....At present, treatment of leukaemia is based either on established chemotherapeutic drug treatment or newly identified inhibitor drugs currently being tested as part of clinical trials. Both these treatments are known to induce or select for resistance to the drugs in some cases. Resistance usually reduces the success rate of any further treatment with the same or similar drugs. To discover possible ways of overcoming drug resistance it is important to understand the mechanisms that are responsible. To date a number of mechanisms that cause resistance are known, but there are still unidentified mechanisms that are associated with drug resistance. The aim of our work is to use a new method to identify unknown drug resistance mechanisms in leukaemia. Once a mechanism is identified, we will determine its relevance in leukaemia by screening a number of patients that have shown resistance to treatment. If identified as a common mechanism of resistance in leukaemic patients, we will test possible agents able to prevent drug resistance that could be used in conjunction with drug during treatment, and to screen new drugs for susceptibility to resistance mechanisms. Diagnostic tests to detect the presence of the known resistance mechanisms prior to treatment could be used in selection of the most appropriate drug combinations for individual patients. Some of the known drug resistance mechanisms that occur in leukaemia are also operative in other forms of cancer and the project is of general relevance to cancer chemotherapy.Read moreRead less