Cancer is the result of multiple genetic errors, involving both the overactivity of growth-stimulating oncogenes and the loss of tumour suppressor genes. The identification of the genes in both of these categories is important if we are to understand and intervene in the disease. Tumour suppressors are the more difficult to identify, precisely because they are lost in cancer cells. Normally the task is extremely time consuming, tedious and expensive. We have developed a system which will provide ....Cancer is the result of multiple genetic errors, involving both the overactivity of growth-stimulating oncogenes and the loss of tumour suppressor genes. The identification of the genes in both of these categories is important if we are to understand and intervene in the disease. Tumour suppressors are the more difficult to identify, precisely because they are lost in cancer cells. Normally the task is extremely time consuming, tedious and expensive. We have developed a system which will provide a short-cut to the cloning of one such gene. We have started with the mouse version, which is lost in leukemic cells. We have mapped the gene to within a very small chromosomal region, and we have identified a biological effect which correlates with loss of the gene. Our next step is to combine these two approaches to clone the gene. Because these genes are always highly conserved between species, we will be able to quickly clone the corresponding human gene, the loss of which is very likely to be important in cancer of various types.Read moreRead less
Analysis Of Intracellular Signalling And Biological Activities Of The GM-CSF Receptor Family Using Constitutive Mutants
Funder
National Health and Medical Research Council
Funding Amount
$505,699.00
Summary
The cytokines GM-CSF, IL-3 and IL-5 stimulate the growth and actions of a wide range of blood cells. Each binds to a receptor on the cell surface which then triggers the generation of a number of signals inside the cell; it is these signals that are responsible for the cytokine?s actions. We have previously generated a panel of constitutive mutant forms of the beta subunit which is shared by the GM-CSF, IL-3 and IL-5 receptors. These constitutive mutants trigger signals even in the absence of th ....The cytokines GM-CSF, IL-3 and IL-5 stimulate the growth and actions of a wide range of blood cells. Each binds to a receptor on the cell surface which then triggers the generation of a number of signals inside the cell; it is these signals that are responsible for the cytokine?s actions. We have previously generated a panel of constitutive mutant forms of the beta subunit which is shared by the GM-CSF, IL-3 and IL-5 receptors. These constitutive mutants trigger signals even in the absence of the cytokine; importantly, the different mutants appear to trigger only a subset of the signals generated by the normal receptor. The aim of this project is to use our panel of constitutive beta subunit mutants to determine how the GM-CSF, IL-3 and IL-5 receptors generate signals inside the cell and how these signals lead to the various biological actions of the receptors on blood cell growth and maturation. Findings from this research will be relevant to the understanding and treatment of diseases which involve abnormal growth or function of blood cells such as leukaemia and inflammatory diseases.Read moreRead less
The Characterization Of A Novel Pseudokinase Regulator Of Platelet Formation
Funder
National Health and Medical Research Council
Funding Amount
$372,965.00
Summary
Mammalian cells contain a complex switchboard, which directs the cell to grow, die, multiply or move in response to external cues. When communication breaks down within the cell, diseases arise. Our studies are directed towards identifying the molecules that comprise the switchboard which directs blood cell formation. A detailed understanding of the regulators of blood cell formation will equip us with a sound starting point for designing drugs to ameliorate blood diseases.
We propose to use a number of genetic approaches to identify key mutations involved in Polycythemia vera. We will analyse patient material, use cell lines and mouse models to investigate any new mutations. We also aim to dissect the role of an important blood cell surface receptor and its cooperation with the mutation in JAK2 recently shown to be important in this disease. These approaches will lead to better understanding of the disease and potential new diagnostic and drug strategies.
CD164: A Sialomucin Adhesion Molecule With Potent Growth Inhibitory Properties
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Blood cell production in the adult mammal is normally restricted to the bone marrow. The ongoing production of blood cells is well regulated and dependent on the controlled proliferation and development of rare, multipotent precursors cells commonly termed stem cells. The blood forming stem cells exist in intimate contact with other cells and tissues that comprise the red bone marrow tissue. It is currently thought that stem cell localisation, survival and growth within the bone marrow is, in pa ....Blood cell production in the adult mammal is normally restricted to the bone marrow. The ongoing production of blood cells is well regulated and dependent on the controlled proliferation and development of rare, multipotent precursors cells commonly termed stem cells. The blood forming stem cells exist in intimate contact with other cells and tissues that comprise the red bone marrow tissue. It is currently thought that stem cell localisation, survival and growth within the bone marrow is, in part, regulated by specific interactions between the stem cells and neighbouring cells or the biochemical products of these cells. Stem cells use specific cell surface structures or cell adhesion molecules to mediate these important interactions. This project seeks to investigate the role in blood cell production, of a specific cell surface molecule, CD164, a member of a larger family of molecules with similar structural features thought to be involved in inhibition of cell growth. The main focus of the project is to identify a ligand or binding molecule for CD164. This information will allow an investigation of the consequences of binding between CD164 and its ligand by stem cells. It is proposed that the CD164-ligand interaction is one of a number of important inhibitory interactions used to regulate proliferation of stem cells. These studies will be greatly facilitated by the generation of a mouse lacking CD164.Read moreRead less
Identification Of Oncogenes From Myeloid Leukaemias By Retroviral Expression Cloning
Funder
National Health and Medical Research Council
Funding Amount
$552,000.00
Summary
The success rates for treatment of most myeloid leukaemias remain relatively poor, with 5-year survival rates of 40-50% overall. Thus there is a clear need for improvements in diagnosis and particularly treatment. An important and relatively new approach for doing this is to target the specific molecular and genetic alterations that lead to these diseases. This requires the identification of these alterations, particularly the oncogenes ('cancer genes') that cause or contribute to the various fo ....The success rates for treatment of most myeloid leukaemias remain relatively poor, with 5-year survival rates of 40-50% overall. Thus there is a clear need for improvements in diagnosis and particularly treatment. An important and relatively new approach for doing this is to target the specific molecular and genetic alterations that lead to these diseases. This requires the identification of these alterations, particularly the oncogenes ('cancer genes') that cause or contribute to the various forms of myeloid leukaemia. However in many cases (up to 50%), the key oncogenes involved in have not and-or cannot be identified using current methods. This project aims to develop and apply a powerful technique called 'retroviral expression cloning' for the identification of oncogenes involved in myeloid leukaemia. In essence our approach is to identify oncogenes from myeloid leukaemia samples on the basis of their function - that is, by virtue of their ability to induce dysregulated or uncontrolled growth of blood-derived cells in culture.Read moreRead less
The Role Of A Phosphorylated Ser/Tyr Bidentate Motif In Leukemia And Myeloproliferative Disorders
Funder
National Health and Medical Research Council
Funding Amount
$279,254.00
Summary
The ability of a normal cell to survive and grow is subject to tight control. Cancer cells escape both these controls and survive and grow in an deregulated manner. Many therapies that are in clinical use or in pre-clinical development target the growth of cancer cells. While such an approach has the advantage of being highly effective in stopping the advance of cancer cell growth, it may allow the long-term survival of some cancer cells and increase the possibility that these cells will become ....The ability of a normal cell to survive and grow is subject to tight control. Cancer cells escape both these controls and survive and grow in an deregulated manner. Many therapies that are in clinical use or in pre-clinical development target the growth of cancer cells. While such an approach has the advantage of being highly effective in stopping the advance of cancer cell growth, it may allow the long-term survival of some cancer cells and increase the possibility that these cells will become resistant to drug treatment leading to disease relapse. On the other hand, therapies that target the survival of malignant cells would be expected to pull the rug from underneath cancer by killing the malignant cells regardless of whether they are growing or not. We have identified a signalling device in normal blood cells that controls both the growth and survival of cells. This device is in effect a switch with 2 components both of which are normally turned on and off. These 2 components are differentially wired to to the cell transmitting unique signals. Importantly, we have found that this switch is faulty in blood cancers and is permanently on in some leukemias promoting their prolonged life-span. Targetting specific components of this unregulated switch may provide new and improved approaches for the development of therapeutics in the treatment of leukemia.Read moreRead less
Neurodegeneration In The Ageing Brain: How The Pathways Leading To Aggregated Protein Cause Disease
Funder
National Health and Medical Research Council
Funding Amount
$12,322,838.00
Summary
The team consists of eight highly experienced research scientists who are dedicated to solving the question of how the brain degenerates in the elderly when associated with the accumulation of certain proteins: e.g. A_ amyloid (Alzheimer�s disease) and PrP (Creutzfeldt-Jakob disease). Understanding the molecular pathways leading to the degeneration (loss of neuronal synapses) will permit the development of rational diagnostic and therapeutic interventions. Over the past five years the program ha ....The team consists of eight highly experienced research scientists who are dedicated to solving the question of how the brain degenerates in the elderly when associated with the accumulation of certain proteins: e.g. A_ amyloid (Alzheimer�s disease) and PrP (Creutzfeldt-Jakob disease). Understanding the molecular pathways leading to the degeneration (loss of neuronal synapses) will permit the development of rational diagnostic and therapeutic interventions. Over the past five years the program has identified several diagnostic and therapeutic avenues which are now being developed by the Pharmaceutical and Biotechnology industries. Much more research is still required for maximizing the chances of success using these approaches.Read moreRead less
The Prevalence And Trajectory Of Kidney Disease In Urban Aboriginal Children
Funder
National Health and Medical Research Council
Funding Amount
$94,515.00
Summary
The Study of Environment and Aboriginal Resilience on Child Health is a major NHMRC funded project looking at the health and illness of urban Aboriginal children in Australia. By working together with Aboriginal Community Controlled Health Services across urban and large regional centres in NSW the study team hope to better understand the causes of common diseases such as kidney and heart disease, and whether these first begin in childhood.