This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflamma ....This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflammatory events. They are known to be important in allergy and infection and have a proposed role in chronic inflammatory processes. Although the mechanisms of mast cell activation contributing to acute responses in allergic reactions are well accepted, ways in which they are activated in asthma and other chronic inflammatory disease are virtually unknown. We will use lung biopsies from patients with asthma to detect patterns of expression of the protein and determine its effects on lung mast cells. A murine model will be used to define the characteristics of inflammation induced by the S100 protein and the role of mast cells in this process. Structural studies will define the parts of the protein necessary for mast cell activation. We will attempt to identify its receptor on mast cells to enable future studies to define how the protein triggers the cells to produce mediators such as histamine and those causing blood vessel changes. This knowledge could lead to design of novel drugs that could regulate this process. Results from this project will provide new knowledge of chronic inflammatory processes and could result in designing novel strategies to regulate these. Studies are relevant to infectious diseases and many other conditions with a chronic inflammatory basis, including asthma, rheumatoid arthritis, cardiovascular disease, cystic fibrosis and infection.Read moreRead less
The Role Of Cbl Proteins In Mast Cell Signalling And Function.
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Allergies such as asthma are caused by cells known as mast cells and basophils. These cells cause allergies because they possess pre-formed granules that contain mediators of allergic reactions, such as histamine, which are released when the cells are activated by allergens. Understanding how this activation occurs, and the biochemical mechanisms that allow the release of allergic mediators, are important steps towards identifying ways to intervene and control allergic responses. The key event t ....Allergies such as asthma are caused by cells known as mast cells and basophils. These cells cause allergies because they possess pre-formed granules that contain mediators of allergic reactions, such as histamine, which are released when the cells are activated by allergens. Understanding how this activation occurs, and the biochemical mechanisms that allow the release of allergic mediators, are important steps towards identifying ways to intervene and control allergic responses. The key event that activates the release of allergic mediators is the binding of environmental allergens to a particular type of antibody called IgE that can bind to a specific receptor on the surface of mast cells and basophils. These IgE-bound receptors transmit strong biochemical signals into the cell which causes a cascade of events resulting in many proteins being biochemically modified and recruited to sites of functional activity. One group of proteins, known as tyrosine kinases, are at the front line of this cascade and they function by targeting and modifying a wide range of other proteins so they become functionally active. Indeed if it were not for tyrosine kinases there would be no signal leading to degranulation of mast cells and basophils and therefore no allergic reactions. Therefore if it were possible to regulate the activity of tyrosine kinases we would be able to control the severity of allergic reactions. For many years we have been studying a protein called Cbl that functions in cells to negatively regulate many tyrosine kinases, including those present in mast cells and basophils. In this grant we aim to investigate whether by deregulating Cbl function in mast cells, derived from mice with mutated forms of Cbl, we can change the activity of tyrosine kinases and thus alter the magnitude of allergic responses. This will determine whether Cbl is candidate target protein for controlling allergies.Read moreRead less
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in g ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in general to maintain the correct number of cells in the body. As such, misregulation of apoptosis is associated with the pathogenesis of a wide array of diseases such as autoimmune diseases, many forms of cancer and neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), heart disease, ischaemia and other conditions. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases that target many cellular proteins for specific cleavage. The activation of these proteases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. Various molecules that are involved in the execution and regulation of apoptosis are potentially excellent targets for therapeutic intervention in a number of disorders and will lead to the development of novel drugs for the treatment and prevention of many pathological conditions.Read moreRead less
The Importance Of GM-CSF In Determining The Fate And Function Of Dendritic Cell (DC) Subsets: Resident DC, Inflammatory DC And Suppressive DC.
Funder
National Health and Medical Research Council
Funding Amount
$334,053.00
Summary
The hormone GM-CSF determines how infections are seen by the immune system GM-CSF is a hormone already in use for increasing the production of white blood cells. We have found that it also affects their function, especially that of specialised white blood cells that process infectious materials to be recognised by the immune system. This project aims to detail the effects of GM-CSF on specialised white blood cells.
Remote Ischaemic Preconditioning And Its Effect On Coronary Physiology And Platelet And Leukocyte Activation.
Funder
National Health and Medical Research Council
Funding Amount
$124,608.00
Summary
Remote ischaemic preconditioning (RIPC) is a novel treatment which can improve patient outcomes after a heart attack, undergoing coronary stenting or bypass surgery. The mechanisms by which RIPC confers this cardio-protection is not clear. We will study the effects of RIPC on platelet activity and the flow of blood in the arteries that supply the heart. Understanding RIPC may open new avenues for treatment of patients with coronary artery disease, one of the major causes of death in Australia.
The Role Of The 72 KDa Inositol Polyphosphate 5-phosphatase In Cellular Function.
Funder
National Health and Medical Research Council
Funding Amount
$549,196.00
Summary
Cells respond to external signals and the environment to undergo cell growth, secretion and-or other specialized functions including control of cell death and-or cell size. We have identified a new enzyme (72kDa 5-phosphatase) which resides inside the cell and regulates signals generated by an enzyme called PI3-kinase. Two of the PI3-kinase signals have been demonstrated to regulate the activity of an oncogene involved in breast and ovarian cancer. We aim to determine the specific role each of t ....Cells respond to external signals and the environment to undergo cell growth, secretion and-or other specialized functions including control of cell death and-or cell size. We have identified a new enzyme (72kDa 5-phosphatase) which resides inside the cell and regulates signals generated by an enzyme called PI3-kinase. Two of the PI3-kinase signals have been demonstrated to regulate the activity of an oncogene involved in breast and ovarian cancer. We aim to determine the specific role each of these PI3-kinase signals plays in the activation of the oncogene. In addition the levels of the 72kDa enzyme is altered in some cervical and lymphoma cancers. We will image live cells containing specific fluorescent probes under different conditions and study the activation and location of these probes in order to understand how different PI3-kinase signals are regulated in time and space. In addition to regulating signals that are involved in cancer, PI3-kinase controls signals that are important for proper immune function. Phagocytosis is a biological process where specialised immune cells (macrophages) take up and remove harmful particles such as bacteria or tumour cells from the circulation. This process depends on PI3-kinase and the signals it produces. We will determine whether the 72 kDa enzyme, which is expressed in macrophages, plays a role in regulating these signals during phagocytosis. We have shown that the 72 kDa enzyme can interact with several different proteins which may affect its location and activity within the cell. We will examine the effect of these interactions on the PI3-kinase signals which are involved in cell survival and immune responses. We will study the function of the enzyme in the intact animal by producing mice which lack this enzyme. Given the possible role of this enzyme in cancer, these mice will be examined for their susceptibility to develop tumours.Read moreRead less
I am a biochemist and molecular pharmacologist discovering and determining the mode and site of action of bioactive peptides from cone snails. I guide the assay and chemical detection of new bioactives which are isolate to purity, sequenced and their stru
Malaria is characterised by defective T cell responses, particularly suppressed T cell growth. T cells are critical to malaria protection and defective immune responses are likely to benefit the parasite. We want to find out how immune-responses are turned off in malaria, so that then we can do something about this, and help fight off the parasite. Malaria kills over 2 million children each year and there is no effective vaccine. We have two important clues as what may be happenning to cause sup ....Malaria is characterised by defective T cell responses, particularly suppressed T cell growth. T cells are critical to malaria protection and defective immune responses are likely to benefit the parasite. We want to find out how immune-responses are turned off in malaria, so that then we can do something about this, and help fight off the parasite. Malaria kills over 2 million children each year and there is no effective vaccine. We have two important clues as what may be happenning to cause suppressed T cell growth during malaria infection. Firstly, we found a massive increase in T cells expressing a surface molecule called CD38 duirng infection. Increases in these cells correlated with decreases in the ability of the T cells from the animals to grow. Indeed, other researchers had observed that in mice CD38 T cells can suppress immunity. Secondly, we hypothesized that they may be responsible for the impaired T cell reactivity observed during acute malaria, and the general poor state of immune responses in humans living in areas where they are being constantly infected by the parasite. Indeed, when we removed cells expressing CD38 from blood cells from such individuals, these 'recovered' and were able to grow much better in our assays. Therefore we propose that CD38 T cells are importnat mediators of malaria immuno-suppression. We now want to understand how the parasite induces these CD38 T cells, and how their ability to suppress T cell responses can benefit the parasite. Knowing this we aim to develop vaccines which can avoid being turned off by malaria. T cells expressing CD38 are also increased in cancer and acute viral disease, such as late stage HIV. Understanding their role in malaria will also give us new clues to fight such diseases.Read moreRead less