Translational Study Of The Genetics Of Systemic Autoimmunity Based On Mouse Mutagenesis
Funder
National Health and Medical Research Council
Funding Amount
$518,500.00
Summary
Lupus is the prototypic autoimmune disease. It is characterised by inflammation that can damage virtually any organ in the body. This inflammation is the outcome of a complex interplay between the environment and genetic predisposition, resulting in production of antibodies against components of normal tissue. Better characterisation of the genetic basis of lupus is a priority because it is the single best path towards a clearer understanding of the mechanism of this debilitating disease, and ul ....Lupus is the prototypic autoimmune disease. It is characterised by inflammation that can damage virtually any organ in the body. This inflammation is the outcome of a complex interplay between the environment and genetic predisposition, resulting in production of antibodies against components of normal tissue. Better characterisation of the genetic basis of lupus is a priority because it is the single best path towards a clearer understanding of the mechanism of this debilitating disease, and ultimately, new therapeutic options. Strategies used to identify the genetic basis of human disease fall into two categories. The first involves gathering genetic information from families with more than one affected member, which is then compared with genetic information from unaffected people. This can identify genetic regions likely to contain disease-causing genes, but so far, this approach has met with limited success in lupus. Although regions of the genome that harbour disease-associated genes have been found, few actual disease causing genes have been confirmed. The second approach begins with known genes that might plausibly cause the disease, based on prior knowledge then tests are performed to see whether particular variants of these genes are more common in patients than in healthy controls. Obviously this approach is usually biased towards investigation of candidate genes that are already well-characterised. In this project, we will combine information obtained from a large-scale mouse-based programme in which genetic changes that cause features of lupus are generated randomly. In other words, there is an unbiased search for candidate genes, which should lead to the discovery of new disease pathways. Since the mouse and human immune systems are remarkably similar, genetic abnormalities that cause features of lupus in mice are highly likely to be informative about the genetic basis of human lupus, a hypothesis we will test with genetic studies in humans with lupus.Read moreRead less
Defining The Immunoregulatory Function Of Roqin: A Novel Gene Essential For Preventing Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$721,250.00
Summary
Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investi ....Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investigations and prediction based on the structure of Roqin, we suspect that this gene may be a key immune regulator. Specifically, it is likely to be involved in maintenance of immunological self-tolerance, which normally prevents development of autoimmunity. Mice carrying the Roqin mutation have an abnormality of their T cells, which causes them to be abnormally activated, divide more readily and survive for longer. Hyperactivated T cells induce B cells to proliferate and secrete antibodies against self-tissues that eventually lead to loss of platelets, kidney damage, enlarged spleen and lymph nodes, and early death. We now want to investigate precisely how Roqin causes abnormal T cell activation. The protein sequence of Roqin predicts the existence of two zinc finger domains that are highly conserved across species and play critical functions in regulating cell growth. One of the zinc fingers is a RING domain known to have a ubiquitin-ligase activity, which is known to play a crucial role in negative regulation of lymphocyte signalling, and maintenance of tolerance. The other zinc finger domain is known to be important for destabilizing mRNA of cytokines, thereby influencing communication between lymphocytes. Elucidation of this novel mechanism of disease will help understand the cause of human lupus. It will also provide clues about more specific drug therapies that might be more efficacious, and carry less toxicity than those currently available.Read moreRead less
Antiphospholipid Antibody-mediated Foetal Loss: Identifying Mechanisms And Developing New Treatments
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Certain immune diseases (Lupus, Anti-phospholipid syndrome) are associated with foetal loss. It is thought to be due to inflammation and blood clotting on the blood vessel lining (endothelium). This proposal will study the mechanisms that stimulate inflammation and blood clotting, and also devise new treatments.
Pathophysiological Mechanisms In The Antiphospholipid Syndrome: B2GPI Regulation Of FXI-FXIa
Funder
National Health and Medical Research Council
Funding Amount
$530,591.00
Summary
The major protein that the antibodies in the antiphospholipid syndrome (APS) bind is called Beta 2-GPI. Antibodies to Beta 2-GPI are associated with recurrent miscarriage, intrauterine growth retardation, clots and stroke. Treatment of patients with the APS are treated with medication that has significant side effects. The development of more targeted and effective therapies for the APS requires a greater understanding of how the antibodies cause their effects, which is addressed in this study.
There has been no significant breakthrough in the treatment of Systemic Lupus Erythematosus (SLE) for over 50 years. Treatment continues to rely on non-specific immunosuppressant drugs and glucocorticoids (GC, or ‘steroids’), and the impact on patients includes high mortality and poor quality of life. In this proposal, I will validate novel endpoints which will break the impasse in SLE drug development and develop tools for minimising GC use in SLE.
How BANK1 Pathway Defects In B Cells Cause Human Lupus
Funder
National Health and Medical Research Council
Funding Amount
$1,316,839.00
Summary
Autoimmune diseases affect 1 in 20 Australians and are incurable. To find effective therapies, we need to understand the genes that cause disease in humans. We have sequenced the entire genome of patients with an autoimmune disease and found several patients carrry two mutations in genes important for activation of B cells and shown these mutations cause disease. We plan to understand how these genes prevent autoimmunity, and to identify the best treatment for patients with these mutations.
Targeting Autophagy As A Means Of Control Of Cytokine Production In SLE
Funder
National Health and Medical Research Council
Funding Amount
$616,518.00
Summary
Systemic lupus erythematosus (SLE, or lupus) is a common immune disease that causes organ damage and loss of life, chiefly affecting young women. There is no cure for SLE. We have discovered that a natural process called 'autophagy' could be a way to limit inflammation during SLE. In this project we will discover whether this could lead to a new way to treat this disease.
Development Of Novel Reagents For The Point-of-care(field) Diagnosis &differentiation Of The Malaria Parasites, Plasmodi
Funder
National Health and Medical Research Council
Funding Amount
$117,000.00
Summary
Malaria is a major global health problem. 500 million people become infected with malaria parasites every year and 2-3 million people die each year from the disease. Rapid diagnosis of the disease is needed to allow correct treatment protocols. Increasingly protein-based immunochromatographic tests are being employed for the diagnosis of malaria as they offer significant advantages over classical thick smear tests, which require trained personnel and laboratory facilities. We propose to develop ....Malaria is a major global health problem. 500 million people become infected with malaria parasites every year and 2-3 million people die each year from the disease. Rapid diagnosis of the disease is needed to allow correct treatment protocols. Increasingly protein-based immunochromatographic tests are being employed for the diagnosis of malaria as they offer significant advantages over classical thick smear tests, which require trained personnel and laboratory facilities. We propose to develop a protein-based malaria diagnostic that has the ability to distinguish the two major human pathogens, P.falciparum and P. vivax.Read moreRead less