A Novel Cytokine-receptor Survival Axis In Chronic Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$424,731.00
Summary
Cancer cells grow and survive in an unrestrained manner. Current therapies target cancer growth, however they permit the long-term survival of some cancer cells and increase the possibility of drug resistance and disease relapse. We have identified a new molecular switch that is constitutively activated (unregulated) in leukemia. Targeting specific components of this unregulated cell survival may provide new and improved approaches for the development of therapeutics in the treatment of leukemia
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
Unraveling IL-1F7: A Neglected IL-1 Family Member With Big-Stage Potential
Funder
National Health and Medical Research Council
Funding Amount
$349,590.00
Summary
Cytokines are messenger proteins used by most cells of the body. Since their role as master regulators of many biological processes was discovered, cytokines have enjoyed the limelight of biomedical research. Anti-inflammatory cytokines are particularly coveted as they could replace side effect-prone anti-inflammatory drugs like aspirin. We identified an anti-inflammatory cytokine (IL-1F7) and revealed its protective activity in common, severe diseases like myocardial infarction. We will now exp ....Cytokines are messenger proteins used by most cells of the body. Since their role as master regulators of many biological processes was discovered, cytokines have enjoyed the limelight of biomedical research. Anti-inflammatory cytokines are particularly coveted as they could replace side effect-prone anti-inflammatory drugs like aspirin. We identified an anti-inflammatory cytokine (IL-1F7) and revealed its protective activity in common, severe diseases like myocardial infarction. We will now explore how IL-1F7 exerts is protective properties.Read moreRead less
Structural Studies On Cell Signalling Via The LIF Receptor And Gp130
Funder
National Health and Medical Research Council
Funding Amount
$453,943.00
Summary
The cytokines play important roles in the immune system during blood cell development and inflammation, and in nerve growth, bone remodeling, reproduction and heart development. Cell responses are initiated by a cytokine bringing together on the cell surface a receptor complex made up of multiple molecules. This project will investigate the atomic structure of the cell surface macromolecular complex, and hence the underlying mechanism by which cytokine signals are initiated.
Regulation Of Innate Immunity And Tumour Progression By Activating Transcription Factor 3
Funder
National Health and Medical Research Council
Funding Amount
$473,469.00
Summary
Toll-like receptors (TLRs) play an essential role in innate immune responses and are involved in initiating tumourigenesis via inflammatory pathways. We have shown that the transcription factor ATF3 is a negative regulator of TLR signalling. We will study how modulation of the activity of ATF3 affects the inflammatory response and tumour progression. This will provide a molecular basis on which to design therapeutic reagents for the treatment of cancer.
The Role Of Suppressor Of Cytokine Signalling-3 (SOCS-3) In Chondrocytes During Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$348,392.00
Summary
Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on the surface of other cells. After binding, a series of intracellular events occurs, termed signalling, that results in the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in various disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of cytokine signalling within the cell. They are induced ....Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on the surface of other cells. After binding, a series of intracellular events occurs, termed signalling, that results in the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in various disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of cytokine signalling within the cell. They are induced by a wide range of stimuli, especially from a group called the IL-6 family. We have preliminary data showing that cartilage cells (chondrocytes) normally produce a particular SOCS protein, called SOCS-3. We have also shown that when SOCS-3 production is dysregulated, the chondrocytes undergo excessive proliferation. Normal chondrocyte function is important during skeletal development and diseases such as osteoarthritis are thought to result from abnormal chondrocyte behaviour. It is likely that SOCS-3 has a key role in regulating chondrocyte function. The aim of this proposal is therefore to examine the role of SOCS-3 in chondrocytes, during development and in disease. Much of our understanding of the role of the SOCS proteins comes from the construction of mutant mice that lack a particular SOCS protein. When mutant mice are made that lack SOCS-3 in the whole animal the mice die before birth and so virtually nothing is known about the role of SOCS-3 in chondrocytes and the implications for cartilage in disease states, such as arthritis. To answer this we will create mice that lack SOCS-3 specifically in their chondrocytes. Evaluating the role of SOCS-3 in cartilage development and chondrocyte function during degenerative and inflammatory disease states is potentially of major clinical importance in improving our understanding of arthritis and of cartilage repair.Read moreRead less
New Mechanisms Of Immunomodulation By Interferon Transsignaling
Funder
National Health and Medical Research Council
Funding Amount
$540,441.00
Summary
The aim of this project is to characterise a new discovery of how the body can regulate its response to disease such as infections and cancer. Interferons are produced by the body to stimulate immune reactions to these diseases. We have dicovered that a circulating form of an interferon binding protein or receptor can change the nature of an immune response. We plan to study how this is achieved and whether this information can be used therapeutically.
Regulating Interferon Signalling In Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$547,428.00
Summary
Our innate immune system evolved as the front line defence against infection. However an uncontrolled response can lead to serious diseases such as septic shock, chronic inflammation as in hepatitis, autoimmune diseases such as systemic lupus erythematosus. The immune respnse is regulated by important hormones such as interferon produced by the body in these situations. This project aims to understand the negative or inhibitory mechanisms that prevent dangerous side effects of interferons withou ....Our innate immune system evolved as the front line defence against infection. However an uncontrolled response can lead to serious diseases such as septic shock, chronic inflammation as in hepatitis, autoimmune diseases such as systemic lupus erythematosus. The immune respnse is regulated by important hormones such as interferon produced by the body in these situations. This project aims to understand the negative or inhibitory mechanisms that prevent dangerous side effects of interferons without restricting their postive or beneficial effects. We will examine the actions of a molecule called the Suppressor of cytokin Signaling 1 (socs1) which we have recently discovered to modulate the actions of interferon in the mouse. Initially our studies will determine which molecules SOCS1 binds to inside a cell and the consequences for cell activation pathways. The next step will be to specifically block this interaction in the mouse and determine the effects on models of viral infection and inflammatory disease. The outcome of these studies will be a better understanding of how the body fights disease via the immune response and potential new approaches to develop therapeutic drugs.Read moreRead less
Altered Gp130-mediated Signalling In The Regulation Of Pulmonary Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$373,956.00
Summary
Pulmonary fibrosis is a chronic diffuse interstitial lung disease often of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation using anti- inflammatory dru ....Pulmonary fibrosis is a chronic diffuse interstitial lung disease often of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation using anti- inflammatory drugs, almost exclusively steroids. The effectiveness of steroids is variable although generally poor and can be associated with significant side effects suggesting that other approaches need to be considered. Data generated over the past decade also have established the concept that the molecular processes underlying the development of fibrosis may represent a new opportunity for therapeutic intervention. This project will build on previous studies examining the effects of a family of molecules called cytokines that signal through gp130 as critical determinants of disease susceptibility and progression. gp 130 is a shared component in the receptor complexes for IL-6 family cytokines and can signal down two major pathways. We have shown that the development of lung fibrosis depends on which specific signalling pathway is used. This study will determine how fibrosis is controlled by these pathways. Our data raises the possibility of developing pharmacological manipulators of gp130 signalling pathways that would suppress fibrosis but leave normal cellular defense mechanisms necessary for host defense in the lung intact.Read moreRead less