A Novel Mode Of Cytokine Receptor Assembly And Activation: Functional And Structural Characterization
Funder
National Health and Medical Research Council
Funding Amount
$621,322.00
Summary
This proposal will study a group of protein hormones and their receptors, implicated in blood cell cancers and inflammatory diseases and for which current treatments are inadequate. We will determine the mechanism of receptor activation and in particular will seek to link different forms of receptor assembly to different functions. This information will help us develop new drugs with more specificity for certain hormone functions and thus less side effects
Development Of A Generic Strategy For The Stabilisation Of Peptide-based Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$443,196.00
Summary
There is huge interest in the development of bioactive peptides and proteins for the treatment of a wide range of diseases. However, there are still a number of hurdles that need to be overcome before this source of promising pharmaceuticals can fulfil their vast potential. One of the biggest challenges in the development of peptides and proteins as drugs is overcoming their poor stability in the human body. The broad aim of this research proposal is to develop a novel strategy that provides the ....There is huge interest in the development of bioactive peptides and proteins for the treatment of a wide range of diseases. However, there are still a number of hurdles that need to be overcome before this source of promising pharmaceuticals can fulfil their vast potential. One of the biggest challenges in the development of peptides and proteins as drugs is overcoming their poor stability in the human body. The broad aim of this research proposal is to develop a novel strategy that provides therapeutically promising peptides and proteins the ability to resist the body s natural degradation pathways so they are able to reach their biological target. To develop this strategy we will use the recently discovered peptide hepcidin as a model system. Hepcidin is the major iron-regulatory hormone in the human body and incorrect levels of this hormone result in either iron overload (haemochromatosis), when there is not enough hepcidin produced by the body, or anemia of inflammation when there is too much hepcidin. The development of hepcidin-based therapeutic agents to treat these conditions has the potential to have significant impact as it has been estimated that up to 1 in 300 Australians are affected by haemochromatosis during their lifetimes. Unfortunately, unmodified peptides, like hepcidin, are of limited therapeutic value due to their poor stability within the human body. This research proposal describes the development of stabilised hepcidin analogues with the potential of being useful drug leads for the treatment of haemochromatosis.Read moreRead less
How Does Basal Chromatic Structure Predict Cytokine Gene Responses?
Funder
National Health and Medical Research Council
Funding Amount
$521,961.00
Summary
To recognise foreign pathogens and eradicate them from the body, immune cells need to quickly switch on genes encoding factors which communicate between cells and drive the immune response. Incorrect expression of these genes contributes to immune diseases such as asthma, arthritis and leukaemia. The aim of this project is to study how the DNA environment of immune genes controls their ability to be switched on and off, and how altering this environment leads to incorrect gene expression.
Macrophage Migration Inhibitory Factor (MIF): Pathological And Therapeutic Significance In Post- Infarct Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$547,577.00
Summary
Ischemic heart injury mediated by the inflammatory response has a significant impact on the prognosis. MIF is a central factor mediating and amplifying the inflammatory response but its role in heart disease remains largely untested. This project will study, for the first time, the crucial role of MIF in ischemic heart disease and will establish important experimental evidence for developing new anti-inflammation therapeutic strategies against ischemic heart injury.
T cells are a central component of the immune system and without T cells the body is very vulnerable to infections. One subgroup of T cells is the killer T cells that are important for identifying and killing cells infected by viruses and bacteria. The immune system works to maintain T cell numbers at a fairly constant level and part of this process includes sending signals to the killer T cells from other cells via cell surface protein interactions and soluble mediators, such as cytokines. We h ....T cells are a central component of the immune system and without T cells the body is very vulnerable to infections. One subgroup of T cells is the killer T cells that are important for identifying and killing cells infected by viruses and bacteria. The immune system works to maintain T cell numbers at a fairly constant level and part of this process includes sending signals to the killer T cells from other cells via cell surface protein interactions and soluble mediators, such as cytokines. We have been studying killer T cells, which are missing a protein SOCS1. SOCS1 is important for switching off the signals generated by a group of cytokines. As a consequence of being unable to correctly regulate cytokine signals these killer T cells multiply inappropriately and contribute to disease development. Our current work is aimed at achieving a better understanding of the particular interactions between killer T cells and other immune system cells and the soluble factors that deliver important signals for maintaining killer T cells in the immune system. The ability to better understand the factors controlling the maintenance of killer T cells will enable us to more intelligently target the immune system ,which is important for improving vaccine strategies and cancer immunotherapy as well as for controlling T cells that are activated inappropriately, such as in autoimmune disease.Read moreRead less
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
Structure-based Design Of Inhibitors Of Oxidative Protein Folding In Enterobacteriaceae.
Funder
National Health and Medical Research Council
Funding Amount
$523,540.00
Summary
Antibiotic resistance represents a major public health problem. For gram-negative bacteria in particular, the situation is increasingly bleak, with the accumulation of resistance to existing drugs and few if any new drugs in the pipeline. We are using structure-based drug design to develop novel strategies for the treatment of gram-negative bacterial infections.
Exploitation Of Bacterial Transcription Initiation As A Target For New Antimicrobials
Funder
National Health and Medical Research Council
Funding Amount
$540,356.00
Summary
Antibiotic resistant infections from 'superbugs' are a major health problem. We will exploit information we have gathered on the machinery that copies genetic information into a message to discover chemical compounds that can be used for the development of new antibiotics with a novel mechanism of action.
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