Protein Recognition Of Small RNAs In Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$666,417.00
Summary
Protein-RNA interactions are critical in the immune response to virus infections. Small interfering RNAs (siRNAs) are important tools in the discovery of gene function and have great potential for therapy against viral infections and cancer, but can also activate the innate immune system. By characterising the determinants of small RNA sensing by the sensors of the immune system and the protein-RNA interactions involved, we will gain new insights into the design of siRNAs for use in the clinic.
Regulation Of Arthritis And Skin Inflammation By Annexin-1
Funder
National Health and Medical Research Council
Funding Amount
$612,885.00
Summary
Annexin-1, an antiinflammatory substance, mediates many of the actions of steroids. Our studies will reveal whether annexin-1 will reduce inflammatory and immune responses, and secondly, determine the substances regulated by annexin-1 in immune responses. If annexin-1 is found to mediate the immune regulatory effect of steroids, its capacity to be involved in the beneficial effect of steroids may have an important impact in treatment of arthritis and other inflammatory diseases.
Regulation Of Leukocyte Trafficking By Macrophage Migration Inhibitory Factor (MIF).
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
The entry of white blood cells in to tissues is a primary event which drives tissue and organ damage in a number of inflammatory and immune mediated conditions. Diseases as diverse as rheumatoid arthritis, lupus or shock due to bacterial infection (septic shock) have many different triggers and manifestations. However almost all autoimmune and inflammatory diseases have one common feature: white blood cells must leave the blood and enter tissue in order to cause tissue inflammation and ultimatel ....The entry of white blood cells in to tissues is a primary event which drives tissue and organ damage in a number of inflammatory and immune mediated conditions. Diseases as diverse as rheumatoid arthritis, lupus or shock due to bacterial infection (septic shock) have many different triggers and manifestations. However almost all autoimmune and inflammatory diseases have one common feature: white blood cells must leave the blood and enter tissue in order to cause tissue inflammation and ultimately tissue damage and loss of function. The mechanism whereby white blood cells leave the blood stream and cross blood vessel walls to get into tissues is a multi-step process often referred to as white blood cell trafficking. Most of the current treatments for immune and inflammatory conditions have the primary aim of keeping white blood cells out of tissue in order to prevent damage. Some of these treatments, like steroids (cortisone), are very effective but cannot be used for prolonged periods because of the risk of problems like bone thinning (osteoporosis), high blood pressure or diabetes. Other treatments and immunosuppressive agents can also be effective but are themselves associated with toxicity and risk of organ damage. Although substantial progress has been made in the management of immune and inflammatory conditions in the last 50 years, the current treatment options are far from ideal. Macrophage migration inhibitory factor (MIF) is an inflammatory substance released by cells which comprise the blood vessel wall as well as by white blood cells themselves. It is known to contribute to the build up of white blood cells in inflamed tissue. The effect of MIF on white blood cell trafficking has never been examined. Understanding how MIF promotes white cell entry in to tissues could be crucial in our understanding of this important process and blocking MIF may prove to be a useful and effective way to prevent it.Read moreRead less
Epigenetic Regulation Of Lymphoid Cell Development And Function
Funder
National Health and Medical Research Council
Funding Amount
$631,950.00
Summary
Inflammatory diseases such as multiple sclerosis, inflammatory bowel disease and asthma are caused by unregulated white blood cells called CD4 T cells. Why certain people develop hyperactive CD4 T cells is not clear but a understanding how CD4 T cells are regulated will help inform future therapies. Our research focuses on one enzyme called G9a that modifies proteins that control immune cell function. Our goal is to define the role of this enzyme in inflammation to aid in drug development.
IgA Mediated Activation Of FcalphaRI, An Fc Receptor And A Leukocyte Ig-like Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$535,500.00
Summary
Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites, these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate with the outside and are the major route of pathogen entry into the ....Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites, these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate with the outside and are the major route of pathogen entry into the body. Here IgA forms a rather passive, but pathogen specific, sticky barrier to prevent microbial pathogens attaching to these large surfaces. In an everyday analogy this IgA behaves somewhat like fly-paper. This subdued response is appropriate as we are constantly exposed to micro-organisms living in our gut, or breathed into our lungs, and our immune system would make us ill if it aggressively attacked our innocuous microbial neighbours. The second type of IgA is found in the blood where it attaches to pathogens that have breached the body's barriers. These IgA tags are actively sought by white blood cells whose function is to protect the body from infection by recognising and engulfing the tagged pathogens and destroying them with killer molecules, including bleach. The IgA-Fc receptor is the sensor on the surface of white blood cells which seeks the IgA tags as they attach to pathogens. In order to survive in this hostile environment some of our pathogens, such as Staphylococcus, have their own strategies to make themselves invisible to the immune system. These strategies include cutting up the IgA tags or blocking the sensors for IgA. In this project we will study how IgA tags turn on white blood cells to destroy pathogens. We will also be looking at two Staphylococcal proteins which block up the sensor for IgA tags. Finally we are endeavouring to understand how it is the mucosal type IgA does not activate the white cells nearly as much as the IgA from the blood.Read moreRead less
Immune Regulation, Cellular Trafficking And Chemokine Receptors In Intestinal Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
The intestine is exposed to a vast array of foreign substances, or antigens, from food to the abundant bacteria that populate the gut. The gut immune system has developed elaborate and poorly understood mechanisms for preventing inflammation in response to these antigens. A breakdown in these control mechanisms may be partly responsible for the chronic intestinal diseases known as inflammatory bowel diseases, which cause abdominal pain, diarrhoea and bleeding. A recently described immune cell ty ....The intestine is exposed to a vast array of foreign substances, or antigens, from food to the abundant bacteria that populate the gut. The gut immune system has developed elaborate and poorly understood mechanisms for preventing inflammation in response to these antigens. A breakdown in these control mechanisms may be partly responsible for the chronic intestinal diseases known as inflammatory bowel diseases, which cause abdominal pain, diarrhoea and bleeding. A recently described immune cell type, known as a regulatory T cell (T reg), is a powerful candidate cell as a master controller of intestinal inflammation. We know that T cells move to various sites in the body under the influence of hormone-like proteins known as chemokines, but the existence of T reg cells in the intestine, their characteristics, their behaviour and their specific response to chemokines, are all unknown. These studies aim to examine the presence and nature of T reg cells in human and mouse intestine, in both health and inflammation, and to explore how these cells migrate into the gut under the influence of chemokines. This knowledge will help in our understanding of intestinal immunity and endogenous regulation of immune responses, and will provide new targets for treatment of inflammatory bowel disease, and potentially other inflammatory diseases.Read moreRead less
Ion channels are complex proteins that regulate salt transport in cells. We have previously cloned, and have been studying, an unusual ion channel called CLIC1, whose function is uncertain. Recent data suggests it is located in areas of white cells that are involved in regulating inflammation and mice lacking CLIC1 are protected from some immune disorders. We wish to determine the role and mechanisms whereby CLIC1 regulates immune and inflammatory responses.
Towards Selective Targeting Of HDACs For Anti-inflammatory Applications
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
HDAC inhibitors are anti-cancer drugs that kill rapidly growing cells (like cancer cells). These drugs also have anti-inflammatory properties and so may be beneficial in chronic inflammatory diseases such as as Rheumatoid Arthritis. However, it is unknown how they reduce inflammation. In this project we aim to understand how HDAC inhibitors act as anti-inflammatory agents and to design new HDAC inhibitors with reduced side effects for the treatment of inflammatory diseases.