Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune diseases. An agent that could block the effects of C5a could be very useful clinically. There is no such drug available as yet. We have developed powerful agents which specifically block C5a in laboratory tests on isolated cells and tissues, and now propose to test their effectiveness in rats in which the above human disease conditions are mimicked. Our preliminary results are very promising, and we will conduct further testing to determine the scope of the actions of the new drugs. One of our new agents is orally active in rats, and we will determine how the blood levels of the drug relate to its beneficial effects. We are also planning to develop agents that are more effective when given by mouth. The results could lead to a new type of anti-inflammatory drug for humans suffering from a variety of diseases that are poorly treatable at present.Read moreRead less
C3/C5 Convertase Inhibitors As A New Class Of Anti-Inflammatory Drugs
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
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. Three complement proteins known as C3a, C5a and MAC (membrane attack complex) are thoug ....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. Three complement proteins known as C3a, C5a and MAC (membrane attack complex) are thought to be particularly pivotal components of the complement system synthesized by the human body early in the development of inflammatory and immune diseases. New compounds that could block the formation of human C3a, C5a and MAC are expected : (a) To lead us to a better understanding of how these proteins act on immune cells and of their respective roles 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 in man. In other NHMRC funded work we have developed compounds (antagonists) that selectively block the actions of human C3a or C5a, and shown that they are effective antiinflammatory agents in rat models of a number of inflammatory diseases. In this project we will design and develop small molecules that block the enzymes (C3-C5 convertases) that make C3a, C5a and other complement proteins including MAC. We expect that such inhibitors will be even more effective antinflammatory drugs because they will block formation of multiple complement proteins that each have proinflammatory activity. We will demonstrate selective effects of the new compounds on components of complement, and test them in rat models of inflammatory diseases. We expect C3-C5 convertase inhibitors to be a completely new type of anti-inflammatory drug, treating disease processes rather than symptoms like current drugs.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
Neurodegeneration In The Ageing Brain: How The Pathways Leading To Aggregated Protein Cause Disease
Funder
National Health and Medical Research Council
Funding Amount
$12,322,838.00
Summary
The team consists of eight highly experienced research scientists who are dedicated to solving the question of how the brain degenerates in the elderly when associated with the accumulation of certain proteins: e.g. A_ amyloid (Alzheimer�s disease) and PrP (Creutzfeldt-Jakob disease). Understanding the molecular pathways leading to the degeneration (loss of neuronal synapses) will permit the development of rational diagnostic and therapeutic interventions. Over the past five years the program ha ....The team consists of eight highly experienced research scientists who are dedicated to solving the question of how the brain degenerates in the elderly when associated with the accumulation of certain proteins: e.g. A_ amyloid (Alzheimer�s disease) and PrP (Creutzfeldt-Jakob disease). Understanding the molecular pathways leading to the degeneration (loss of neuronal synapses) will permit the development of rational diagnostic and therapeutic interventions. Over the past five years the program has identified several diagnostic and therapeutic avenues which are now being developed by the Pharmaceutical and Biotechnology industries. Much more research is still required for maximizing the chances of success using these approaches.Read moreRead less
The Prevalence And Trajectory Of Kidney Disease In Urban Aboriginal Children
Funder
National Health and Medical Research Council
Funding Amount
$94,515.00
Summary
The Study of Environment and Aboriginal Resilience on Child Health is a major NHMRC funded project looking at the health and illness of urban Aboriginal children in Australia. By working together with Aboriginal Community Controlled Health Services across urban and large regional centres in NSW the study team hope to better understand the causes of common diseases such as kidney and heart disease, and whether these first begin in childhood.
Computational Modelling To Understand Early-stage Neurodegeneration
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Rather than attempting to reverse neurodegeneration, therapeutic strategies must target the earliest possible stages of disease, when treatments have the potential to prevent or slow down pathological progression. The proposed project will employ computational modelling using functional MRI to deliver highly efficient and sensitive markers of Familial Alzheimer’s disease and Huntington’s disease progression to inform when in the progression of disease clinical trials should take place.
The Causes, Treatment, And Prognosis Of Thyroid Disease
Funder
National Health and Medical Research Council
Funding Amount
$190,445.00
Summary
The thyroid gland controls body metabolism and is crucial to life. Disorders of the thyroid place a severe burden on the health system. Yet despite this, much is unknown about the causes, optimal treatments, and prognosis of thyroid disease. In this NHMRC Early Career Fellowship, Don aims to advance knowledge and improve treatments of these common conditions, focusing on thyroid cancer, Graves’ disease, and Hashimoto’s thyroiditis.
How The Environment And Epigenetics Affect The Brain Disease Gene, MAPT.
Funder
National Health and Medical Research Council
Summary
Genetic variants in the microtubule associated protein Tau (MAPT) gene are major risk factors for Alzheimer’s disease and Parkinson’s disease. Environmental or lifestyle factors, such as diet and smoking, have crucial roles in changing the risk of developing these diseases. These environmental factors may exert their influence via a mechanism known as "epigenetics". This project aims to determine whether the MAPT gene is susceptible to epigenetic changes by environmental factors, and whether thi ....Genetic variants in the microtubule associated protein Tau (MAPT) gene are major risk factors for Alzheimer’s disease and Parkinson’s disease. Environmental or lifestyle factors, such as diet and smoking, have crucial roles in changing the risk of developing these diseases. These environmental factors may exert their influence via a mechanism known as "epigenetics". This project aims to determine whether the MAPT gene is susceptible to epigenetic changes by environmental factors, and whether this process will have an impact on these diseases.Read moreRead less