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
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
Targeting A Complement Receptor That Regulates Inflammatory Disease
Funder
National Health and Medical Research Council
Funding Amount
$566,946.00
Summary
There are over 100 inflammatory diseases, such as arthritis, inflammatory bowel diseases, sepsis, shock, heart disease, ischemia-reperfusion injury, atherosclerosis, multiple sclerosis, etc. Current antiinflammatory drugs are either not very effective or are compromised by high costs, safety concerns, or reduced effectiveness over time. Complement proteins are natural substances in human blood that protect against infection and injury by causing inflammation which is a desirable component of the ....There are over 100 inflammatory diseases, such as arthritis, inflammatory bowel diseases, sepsis, shock, heart disease, ischemia-reperfusion injury, atherosclerosis, multiple sclerosis, etc. Current antiinflammatory drugs are either not very effective or are compromised by high costs, safety concerns, or reduced effectiveness over time. Complement proteins are natural substances in human blood that protect against infection and injury by causing inflammation which is a desirable component of the immune response. One of these complement factors known as C5a is now thought to be a pivotal component of the complement system of human blood proteins that are synthesized during immune defence against infection. However when C5a is overexpressed or left unregulated it can lead to inflammatory diseases and is now throught to be a key factor in disease progression. In other work, we have been investigating the blockade of various human complement proteins (C5a, C3a, MAC), resulting in a number of new small molecules that can selectively affect, and allow us to probe their specific importance in, the human immune response. This project seeks to develop new compounds (suitable for development into drugs) that can block the binding of C5a to its receptor on the surface of immune cells, thereby preventing the pro-inflammatory actions of C5a. Such compounds have the potential to be new classes of antiinflammatory drugs that treat disease progression rather than just the symptoms of disease. We have previously created the first small molecule antagonists that helped to establish the importance of human C5a in inflammatory disease. We now need to find out how small molecules bind to the receptor for C5a, in order to more effectively block its action in vivo and develop improved antiinflammatory drugs for man.Read moreRead less
Function Of Factor H-related Protein-5, A Novel Human Plasma Complement Protein Found In Glomerular Immune Deposits
Funder
National Health and Medical Research Council
Funding Amount
$186,430.00
Summary
The Investigators have recently discovered a new protein which is present in human blood and is also seen in the diseased kidneys of patients with nephritis. The new protein is present in all types of nephritis that are caused by antibodies together with another part of the immune system, called the complement system, which is know to have an important role in causing tissue damage in immune diseases. The new protein is a part of the complement system but its exact function is not yet known. The ....The Investigators have recently discovered a new protein which is present in human blood and is also seen in the diseased kidneys of patients with nephritis. The new protein is present in all types of nephritis that are caused by antibodies together with another part of the immune system, called the complement system, which is know to have an important role in causing tissue damage in immune diseases. The new protein is a part of the complement system but its exact function is not yet known. The protein is likely to be important in immune diseases because it is so commonly found in diseased kidneys and other organs with complement-associated disease. In this project we will conduct a series of experiments which will determine how the new protein works in the complement system and also how important the protein is in causing kidney damage in nephritis. Nephritis is the commonest cause of kidney failure in Australia and research directed towards the mechanism of kidney damage has the potential to produce new types of therapy. The complement system also has a major role in other inflammatory diseases and in body defense systems (such as protection against microbial attack). The complement system must be able to distinguish between foreign particles and the body's own tissue and this new protein may have a role in the appropriate regulation of complement to attack the right things in the body. Elucidation of the function of this protein may well assist, therefore, in developing therapies for a variety of inflammatory diseases and infectious diseases, in addition to nephritis.Read moreRead less