Role Of Complement Factor H And Related Proteins In Regulating Complement Activation And Microbial Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$377,036.00
Summary
A group of proteins in blood called Complement are activated in the presence of foreign cells or organisms and this generally results in their destruction. It is important to direct this destructive activity against foreign and not self tissue. This is achieved by a further family of proteins, including factor H, which regulate complement activity and how these proteins work is the principal focus of this project. There are many diseases in which damage results from inadvertent complement damage ....A group of proteins in blood called Complement are activated in the presence of foreign cells or organisms and this generally results in their destruction. It is important to direct this destructive activity against foreign and not self tissue. This is achieved by a further family of proteins, including factor H, which regulate complement activity and how these proteins work is the principal focus of this project. There are many diseases in which damage results from inadvertent complement damage and the regulatory proteins have therapeutic potential in this area. In addition many bacteria and other microorganisms, which should be destroyed by complement, escape by binding regulatory proteins. Understanding how this is achieved may reveal new targets for vaccine development. Knowledge of how the production of factor H and related proteins will help understand how inflammation occurs and how it might be controlled.Read moreRead less
STRUCTURAL STUDIES OF KEY REGULATORY PROTEINS OF THE COMPLEMENT CASCADE
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
This work is expected to lead to the determination of the three-dimensional shape of important immune regulatory proteins using X-ray crystallography. In this method, protein crystals are grown and their atomic structure determined by placing them in a beam of X-rays. The crystals cause the X-rays to scatter in a pattern which is characteristic of the protein's three-dimensional shape. Knowledge gained from the proteins' shape provides important insights into their biological function and form t ....This work is expected to lead to the determination of the three-dimensional shape of important immune regulatory proteins using X-ray crystallography. In this method, protein crystals are grown and their atomic structure determined by placing them in a beam of X-rays. The crystals cause the X-rays to scatter in a pattern which is characteristic of the protein's three-dimensional shape. Knowledge gained from the proteins' shape provides important insights into their biological function and form the basis for the rational design of new drugs to combat diseases. In particular, we are interested in determining the 3-D shapes of important proteins that control immunity. Sometimes these proteins can function abnormally resulting in serious diseases such as autoimmune diseases, stroke, Alzheimer's disease, heart attack, haemorrhagic shock, sepsis, adult respiratory distress syndrome, asthma and organ transpant rejection. Thus the ability to provide new drugs has important clinical ramifications in the treatment of these diseases.Read moreRead less
Glomerulonephritis (Bright's Disease) is the commonest cause of destruction of kidney function that leads to patients requiring artificial kidney treatment (dialysis) and renal transplantation. The glomeruli or filters of the kidney are attacked by inflammation and destroyed. The attack is usually auto-immune, that is the bodys' immune system loses tolerance to kidney tissue and mounts a destructive attack on the glomeruli. In many patients, this attack is mild and resolves with current treatmen ....Glomerulonephritis (Bright's Disease) is the commonest cause of destruction of kidney function that leads to patients requiring artificial kidney treatment (dialysis) and renal transplantation. The glomeruli or filters of the kidney are attacked by inflammation and destroyed. The attack is usually auto-immune, that is the bodys' immune system loses tolerance to kidney tissue and mounts a destructive attack on the glomeruli. In many patients, this attack is mild and resolves with current treatments to dampen the immune response. In others, current treatment is inadequate to dampen the attack and the kidney is destroyed. This research uses experimental models of nephritis to examine how the immune system injures the glomeruli. In particular, how T cells attack and mediate injury. This is a novel concept, as hither to it has been thought antibodies and other factors in the blood (complement) mediate injury. Our group was one of the first to identify T cells mediate injury in forms of glomerulonephritis, previously thought to be solely mediated by antibody and complement. This project will further define which molecules produced by the T cell effect injury of glomeruli. With the potential aim of turning off the T cell attack mechanisms in a more specific way than is achieved by non specific immunosuppressive drugs such as corticosteroids, cytotoxic (anti-cancer) drugs or cyclosporine (an anti-rejection drug). A major part of this project will be to examine the role of cytokines, hormone like molecules that are produced by white cells and mediate injury or regulate other white cells, in effecting injury and in turning off the immune injury.Read moreRead less
The Therapeutic Role Of Complement Inhibition In ANCA Associated Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$600,964.00
Summary
ANCA associated vasculitis is an inflammatory disease involving the kidney filters which is a major cause of chronic kidney failure. Current drugs to treat it are toxic. Less toxic treatments are required. In this study we will explore the potential for new treatments targeting complement (a normal blood protein involved in inflammation) to attenuate this disease in mice. We hope to define the role of complement in this disease and the benefits of inhibiting it before we use it in humans.
Contribution Of Complement C5a To Neuronal Cell Death During Ischemic Stroke
Funder
National Health and Medical Research Council
Funding Amount
$455,263.00
Summary
Ischemic stroke remains the second leading cause of death in Australia. This project aims to understand the role the innate immune system plays in neuronal cell death following ischemic stroke. We will use cellular and animal models of ischemic stroke, as well as examine patients affected by stroke, to explore and inhibit potential damaging immune factors generated by stroke tissue. By exploring these immune pathways, we aim to identify novel therapeutic targets to treat ischemic stroke.
Characterisation Of The SCR-domain Family Of Complement Regulators ; Structure, Function And Streptococcal Pathogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
A group of proteins in blood called 'Complement' are activated in the presence of foreign cells or micro-organisms and this generally results in their destruction. It is important that this destructive activity is directed against foreign and not self tissue. This is achieved by a further family of proteins, including a protein called factor H, which switch off or regulate complement activity. How these proteins work is the principle focus of this project. There are many diseases in which damage ....A group of proteins in blood called 'Complement' are activated in the presence of foreign cells or micro-organisms and this generally results in their destruction. It is important that this destructive activity is directed against foreign and not self tissue. This is achieved by a further family of proteins, including a protein called factor H, which switch off or regulate complement activity. How these proteins work is the principle focus of this project. There are many diseases in which damage results from inadvertent complement activation and the regulatory proteins have therapeutic potential in this area. In addition, many bacteria and other micro-organisms, which should be destroyed by complement, escape by binding regulatory proteins. Understanding how this is achieved may assist in identifying targets for vaccine development.Read moreRead less
Evaluation Of Orally Active Anti-inflammatory C5a Receptor Antagonists In A Transgenic Rat Motor Neurone Disease Model
Funder
National Health and Medical Research Council
Funding Amount
$533,578.00
Summary
Motor neurone disease is a rapidly progressive and incurable disease, usually ending in death within 3-5 years of diagnosis. The disease usually arrives without warning, and results in a progressive loss of muscle control. There is no effective treatment, and available drugs increase life span by a few weeks at best. There is evidence that the disease involves an inflammatory component, but available anti-inflammatory drugs are ineffective. We have developed a new class of anti-inflammatory drug ....Motor neurone disease is a rapidly progressive and incurable disease, usually ending in death within 3-5 years of diagnosis. The disease usually arrives without warning, and results in a progressive loss of muscle control. There is no effective treatment, and available drugs increase life span by a few weeks at best. There is evidence that the disease involves an inflammatory component, but available anti-inflammatory drugs are ineffective. We have developed a new class of anti-inflammatory drugs, known as C5a antagonists, and in preliminary experiments have shown they are therapeutically effective in a transgenic rat model of motor neurone disease. We propose to investigate in more detail how these drugs work in the rat model, and demonstrate that a specific inflammatory pathway, which we can now block, is responsible for some of the disease's progression. This work may lead to an entirely new class of drugs being used to treat patients with this drastic disease.Read moreRead less