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The Role Of Hox Genes In Myeloid Cell Development And Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$591,286.00
Summary
The transformation of normal white blood cells into leukaemic cells occurs as a result of changes to the genes of those cells. These changes are often characteristic of particular cancers and carry diagnostic and prognostic significance. This work will determine how critical some of the typical genetic changes of leukaemia are to the occurrence and persistence of cancer. Importantly, we will determine whether targeting these changes can provide new and effective approaches to treatment.
Thymic Epithelial Cell Apoptosis, Aire And Autoimmune Disease.
Funder
National Health and Medical Research Council
Funding Amount
$470,799.00
Summary
Autoimmune diseases, like diabetes and multiple sclerosis are a significant disease burden. Their root cause is the failure of the immune system to distinguish between the body's own tissues and potential pathogens. We propose to study how potentially dangerous immune cells are destroyed in the thymus before they can develop. This research will significantly improve our understanding of how autoimmune diseases begin.
Regulation Of Mitochondrial Fission, Fusion And Distribution
Funder
National Health and Medical Research Council
Funding Amount
$480,128.00
Summary
Mitochondria are subcellular compartments that produce most of the energy for our bodies, in the form of ATP. They were once thought of as small bean-shaped organelles floating around in our cells, but it is now known that mitochondria instead form networks of tubules that undergo changes in their shape through both fission and fusion events. Mitochondria are transported along microtubules that act as highways in the cell so that they can be distributed to areas that require ATP or other special ....Mitochondria are subcellular compartments that produce most of the energy for our bodies, in the form of ATP. They were once thought of as small bean-shaped organelles floating around in our cells, but it is now known that mitochondria instead form networks of tubules that undergo changes in their shape through both fission and fusion events. Mitochondria are transported along microtubules that act as highways in the cell so that they can be distributed to areas that require ATP or other specialist functions such as uptake and release of calcium. In specialist cells, mitochondria are organised even further. Sperm cells contain mitochondria packed around the mid-piece of the flagellum so that ATP can be utilised directly for swimming. Proper mitochondrial distribution also appears to be required for nerve cell development and function while in pancreatic cells they sit at the cell's edge and help regulate the secretion of insulin into the bloodstream. While we now realise the great importance of mitochondria to the cell, we are only beginning to work out how these organelles undergo the drastic morphological changes which are essential for cellular function. Of the few known components involved in shaping mitochondria, some have been found to be essential to life and their gene mutations are linked to neurological disorders, while others appear to be recruited in the activation of cell death pathways. In this application, we plan to identify and characterise the proteins involved in movement and shaping of these organelles. Understanding the fundamental mechanisms of mitochondrial dynamics will provide valuable insights into mitochondrial segregation and specialisation in cells and their defects that lead to disease.Read moreRead less
Synthetic Analogues Of The Actinomycin, Quinamycin And Nogalamycin Groups Of Antitumour Antibiotics
Funder
National Health and Medical Research Council
Funding Amount
$376,433.00
Summary
The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar ....The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar scenario in the treatment of adults with leakaemias and non-Hodgkins lymphomas. The underlying cause of drug resistance is the genetic instability of cancer cells which results in tumours that are heterogeneous, making it almost inevitable that a cancer cell will arise that is resistant to treatment. There are many mechanisms of resistance, some of which are peculiar to particular drug types, some are permeability barriers and some involve genetic deregulation of the biochemistry of cell death. One way of subverting resistance is by the use of drugs whose mechanism of action is novel so that the tumour is challenged to devise a new defense. Here, we are attempting to develop synthetic analogues of a class of naturally- occurring antitumour antibiotic whose mechanism of action is unusual but which has not been exploited by medicinal chemists because of the difficulty of the chemistry involved. These antibiotics work by binding to DNA and inhibiting the first step in the process whereby genes are turned into proteins. We have designed compounds that are chemically accessible that our preliminary work suggests mimic the DNA-binding and biological properties of the natural antibiotics. The proposed work will enable us to evaluate whether this new class of agent has experimental antitumour activity, particularly amongst drug-resistant tumours.Read moreRead less
FOXO Proteins And Protection From Cardiac Ischaemic Injury
Funder
National Health and Medical Research Council
Funding Amount
$354,375.00
Summary
Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the development of heart failure, a major cause of death and disability in western countries. Treatment with growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other tissues. For these reasons, it is necessary to establish ways ....Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the development of heart failure, a major cause of death and disability in western countries. Treatment with growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other tissues. For these reasons, it is necessary to establish ways to activate protective pathways in the heart without causing unwanted effects on other tissues. To this end, we have identified for the first time in the heart members of a newly described family of gene regulators that can cause cell death by increasing expression of cytotoxic factors. We showed that these FKHRor FOXO family members are regulated in the heart and that they are active in generating cytotoxic factors. We now plan to establish whether FOXO proteins are involved in causing cell death during heart attack and whether manipulating their activities can be cardioprotective.Read moreRead less
Regionalisation And Differentiation Of EPL-derived Neurectoderm: Directed Formation Of Dopaminergic Neurons In Vitro.
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Neurodegenerative diseases result from the loss, damage or dysfunction of neural populations. For example, dopaminergic neurons are lost progressively in Parkinson's Disease. A potential method of treatment is 'cell therapy' which envisages transplantation of cells back to the site of cell loss, and restoration of function. Application of the cell therapy approach is limited by the unavailability of cells for transplantation. Embryonic stem (ES) cells provide a potential solution to this problem ....Neurodegenerative diseases result from the loss, damage or dysfunction of neural populations. For example, dopaminergic neurons are lost progressively in Parkinson's Disease. A potential method of treatment is 'cell therapy' which envisages transplantation of cells back to the site of cell loss, and restoration of function. Application of the cell therapy approach is limited by the unavailability of cells for transplantation. Embryonic stem (ES) cells provide a potential solution to this problem because they can be grown in unlimited numbers and differentiated to any kind of cell that is found in the embryo or adult. In this application we propose to continue our work on controlling the differentiation of ES cells to neural lineages. Production of dopaminergic neurons will be a particular focus. We will establish conditions that enable the production of these cells in a manner that is therapeutically relevant and predicted to be acceptable to regulatory authorities. Cells will be tested by transplantation into adult rats to assess their therapeutic potential, in particular persistence, integration and differentiation within the brain environment. Research required to achieve the production of transplantable cells will also provide basic information about the mechanisms by which the mammalian embryo allocates cells, specifically cells of the nervous system, to specific lineages during embryogenesis. This information will be important for the production of other neural cell types, which have therapeutic potential for treatment of diseases like stroke, motor neuron disease and spinal cord injury.Read moreRead less
The Regulation And Role Of Puma And P53 In IL-3 Withdrawal Induced Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$527,683.00
Summary
It is the ultimate fate of most of our cells to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . When cell death fails to occur, abnormal cells can accumulate and lead to cancer. Signalling from growth-factors is required for many cell types to survive. When these signals are lost, the cells activate their cell death pathways. It is a hallmark of cancer cells that they ha ....It is the ultimate fate of most of our cells to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . When cell death fails to occur, abnormal cells can accumulate and lead to cancer. Signalling from growth-factors is required for many cell types to survive. When these signals are lost, the cells activate their cell death pathways. It is a hallmark of cancer cells that they harbour mutations in cell death genes and their dependence on growth factors for survival is diminished or lost. The genes of the apoptosis pathway function either to promote or inhibit cell death. Some genes in the apoptosis pathway allow apoptosis to proceed rapidly, but do not decide the fate of the cell. Other genes are required for a cell to commit to die, and if they are mutated then a functional cell, that is capable of proliferating, survives. This is a crucial distinction because it is only the genes that decide cell fate that can act as cancer genes, and are valid targets for therapy. We have identified one particular gene, Puma, as an important regulator of cell survival. Without this gene, cells survive longer without growth-factor and, importantly, can proliferate when growth factor is restored. Understanding how this gene functions and is regulated will contribute to our understanding of the gene mutations that lead to cancer and may identify valid targets for cancer therapy. In our model we use growth factor dependent cell lines derived from mice lacking particular genes in the cell death pathway, including Puma. These cells proliferate in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn. Using this system, we will determine how Puma is able to induce cell death, what other genes are required to regulate this process and how loss of Puma function may contribute to cancer development.Read moreRead less
Mitochondria: Molecular And Cellular Insights Into Their Diverse Contributions To Neuronal Injury
Funder
National Health and Medical Research Council
Funding Amount
$747,927.00
Summary
Mitochondria are components of cells normally providing energy for essential functions and in the energy demanding brain, under stress conditions, mitochondria acts as controllers of cellular decision-making processes leading to neuronal death. Our goal is to understand mitochondrial mechanisms determining how neurones die after various stresses and injury. Using pathological insults relevant to neurological conditions, we shall analyse death molecules and how neurones adapt when threatened.
The Roles Of Beta-catenin, APC And The Wnt/beta-catenin Pathway In Lens Development And Cataract
Funder
National Health and Medical Research Council
Funding Amount
$456,764.00
Summary
Cataract is a leading cause of blindness. Many risk factors have been identified but the basic cellular and molecular mechanisms that cause cataract are not well understood. Investigation of these mechanisms is essential to identify potential targets for future therapies to arrest or prevent cataract formation. The lens is composed of epithelial and fibre cells. Much of our research has focussed on identifying genes and cell signalling pathways that regulate formation of fibre cells from the epi ....Cataract is a leading cause of blindness. Many risk factors have been identified but the basic cellular and molecular mechanisms that cause cataract are not well understood. Investigation of these mechanisms is essential to identify potential targets for future therapies to arrest or prevent cataract formation. The lens is composed of epithelial and fibre cells. Much of our research has focussed on identifying genes and cell signalling pathways that regulate formation of fibre cells from the epithelial cells. However, considerably less is known about factors that regulate formation of the epithelium itself. As the epithelial cells are affected in some types of cataract it is vitally important to understand the mechanisms that control formation and maintenance of these cells. Our previous studies have identified a growth factor family (TGF-beta) that causes epithelial cataracts. Importantly, our recent studies have identified another growth factor signalling pathway (Wnt-beta-catenin) as being essential for the formation and maintenance of the lens epithelium. We hypothesise that this pathway is disrupted dring cataract formation. This project uses state of the art tools and techniques to investigate the role of two central molecular components of this Wnt pathway (APC and beta-catenin) in the developing lens. By genetically manipulating the activity of these proteins in the mouse lens we will investigate the roles these molecules and the Wnt signalling pathway play in lens development and whether inappropriate activity results in abnormal development or cataract. We will also be able to investigate whether modulating this pathway affects the formation of epithelial cataracts by TGFbeta. The results will provide detailed information on how these molecules regulate lens structure and function and have the potential to identify targets for preventing or ameliorating cataracts.Read moreRead less