Scabies is caused by microscopic mites burrowing through the skin, causing intense itching and providing prime breeding sites for bacteria. The resulting skin sores are very common among Aboriginal children in Australia leading to extreme levels of rheumatic fever-heart disease and renal failure in Indigenous communities. We have discovered mite products termed Serpins which interfere with the patients defence against the mites and the bacteria and aim to develop therapeutics.
Last year an estimated 3.1 million people died of AIDS (source: UNAIDS, Dec 2002) equivalent to the number killed by tuberculosis and malaria combined. AIDS-related opportunistic infections (OIs) are the main cause of death for AIDS patients, especially in resource constrained countries where access to antiretroviral and antibiotic therapy is limited. Attempts to limit the epidemic have failed and new foci have emerged in Eastern Europe, Central Asia and, of particular relevance for us, South Ea ....Last year an estimated 3.1 million people died of AIDS (source: UNAIDS, Dec 2002) equivalent to the number killed by tuberculosis and malaria combined. AIDS-related opportunistic infections (OIs) are the main cause of death for AIDS patients, especially in resource constrained countries where access to antiretroviral and antibiotic therapy is limited. Attempts to limit the epidemic have failed and new foci have emerged in Eastern Europe, Central Asia and, of particular relevance for us, South East Asia, underlining the fact that safe and effective treatment for AIDS-related OIs will be a global health priority for the foreseeable future. People with healthy immune systems do not get OIs since the germs that cause such infections are efficiently ingested and subsequently destroyed by cells called macrophages. We have discovered that the virus that causes AIDS, HIV-1, interferes with the ability of macrophages to ingest opportunistic pathogens by the 2 most important mechanisms used for this purpose. We believe that this is the direct cause for the susceptibility of AIDS patients to many of the opportunistic pathogens that cause their OIs. The purpose of this grant will be to understand the biochemical basis underlying these 2 defects in macrophage function. This will help in the design of safe, adjunctive therapies aimed at improving macrophage function and reducing the risk of HIV-infected individuals developing AIDS-related OIs.Read moreRead less
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
Agonists And Antagonists Of The Human Complement C3a Receptor
Funder
National Health and Medical Research Council
Funding Amount
$473,250.00
Summary
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis, multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that naturally occuring Complement proteins in human blood are involved in exacerbating these and many other human diseases, yet there are no good drugs available to counteract their effects. One of the most important complement proteins is known as C3a. It is called an anaphyla ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis, multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that naturally occuring Complement proteins in human blood are involved in exacerbating these and many other human diseases, yet there are no good drugs available to counteract their effects. One of the most important complement proteins is known as C3a. It is called an anaphylatoxin and is thought to be a pivotal component of the complement system synthesized by the human body early on in the development of inflammatory and immune diseases. New compounds that could stimulate or block the activity of C3a are expected : (a) To lead us to a better understanding of how C3a binds to its receptors on immune cells and its role in the immune response to infection and injury, and (b) To enable the rapid development of an entirely new class of drugs for treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available. It is not yet possible to examine detailed structures of the receptors on cells that interact with complement proteins. However it is possible to determine and analyse three dimensional structures of small molecules that can bind to human immune cells, and mimic or block effects of human C3a on cells, rat tissues, and in whole rats. We will identify and improve such small molecules by optimising their binding to immune cells, by tailoring them to selectively block or mimic just the effects of C3a, and by making them pharmacologically stable for administration (preferably by mouth) to rats (and humans). We will then test them in rats for potential future development into a completely new type of anti-inflammatory drug, one that treats inflammatory disease processes rather than just the symptoms like most current antiinflammatory drugs.Read moreRead less