Antiphospholipid Antibodies, Beta 2-Glycoprotein I And Control Of Coagulation.
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
Antiphospholipid antibodies are associated with an autoimmune condition characterised by the presence of clots and recurrent miscarriages. Although the name implies that the antibodies bind phospholipid the disorder is characterised by circulating antibodies which bind a protein in the blood known as Beta 2-Glycoprotein I. The exact role of Beta 2-GPI in the body has not been determined, although there are numerous studies looking at this protein. This protein has been thought to be important in ....Antiphospholipid antibodies are associated with an autoimmune condition characterised by the presence of clots and recurrent miscarriages. Although the name implies that the antibodies bind phospholipid the disorder is characterised by circulating antibodies which bind a protein in the blood known as Beta 2-Glycoprotein I. The exact role of Beta 2-GPI in the body has not been determined, although there are numerous studies looking at this protein. This protein has been thought to be important in controlling the clotting system in humans and other mammals. The evidence for this has been contradictory, however, we have recently made a major new finding on the function of this protein on the clotting system. We will be using sophisticated molecular biology techniques to further characterise the role that Beta 2-GPI has in controlling clotting factors in the body. We have been able to eliminate the gene for Beta 2-GPI in mice thus deriving mice that do not produce any Beta 2-GPI protein. These mice are called Beta 2-GPI knockout mice and will be an ideal animal model to examine the function of Beta 2-GPI and its new role in controlling the clotting cascade by targetting a specific part of this pathway. In addition, these findings may be able to provide new information on how Beta 2-GPI controls clotting factors and the effect of antiphospholipid antibodies on this system, which may lead to new treatments for antiphospholipid antibodies and more generally clotting disorders.Read moreRead less
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 Cellular And Molecular Mechanisms Underlying Autoimmunity Using A Model Of SLE
Funder
National Health and Medical Research Council
Funding Amount
$624,960.00
Summary
The immune system has to recognize the difference between foreign pathogens, which it should attack, and ourselves, which it should not. Autoimmune diseases, like lupus, occur when our immune systems attack our own tissues due to problems in regulation. We have developed an animal model of lupus that has allowed us to identify major points where immune regulation has failed. Identifying these checkpoints will allow us to design and trial novel therapeutics in lupus.
Identifying The Underlying Mechanisms Responsible For The Generation Of Pathogenic B Cells In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$163,755.00
Summary
Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are r ....Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are responsible for most of the damage to the beta cells in T1D. Recent work in this model, however, has demonstrated that another class of immune cell, termed B cells, also play an important role in T1D as NOD mice made deficient in these cells no longer develop disease. In addition to producing antibodies, B cells are one of the few cell types which are able to take up and present protein fragments in a form recognizable to T cells. Normally, this only leads to the activation of T cells recognising foreign insults, like viruses or bacteria, resulting in their destruction. We have shown that a dangerous population of B cells can arise in NOD mice that can specifically take up beta cell proteins and present them to the T cells, which subsequently become armed to recognise and destroy the beta cells. Just like T cells, B cells that recognize the body's own proteins are normally eliminated in healthy mice and human individuals. This research proposal aims to determine the faulty immune mechanisms that give rise to the beta cell specific B cells in NOD mice. We have also set out to identify the diabetes susceptibility genes which control the generation of this dangerous population of B cells in this model. By understanding how these dangerous B cells are generated in NOD mice, we hope to form the basis for new therapies aimed at inhibiting these cells from forming in T1D susceptible humans, thus preventing the disease at an early stage.Read moreRead less
Src Family Kinases: Regulation Of Phosphoinositol-3 Kinase Signaling And Autoimmune Disease Development.
Funder
National Health and Medical Research Council
Funding Amount
$526,683.00
Summary
The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of, self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune disease includes more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more successful treatments. The Lyn ty ....The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of, self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune disease includes more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more successful treatments. The Lyn tyrosine kinase is an enzyme that is found within blood cells. It participates in transmitting information across the cell membrane to turn off cellular responses. Studies in mutant mice have shown that Lyn is critically important for maintaining stability in the immune system. Mice that are unable to make Lyn protein (Lyn-deficient mice) as well as mice that express an activated form of the Lyn enzyme (Lyn-up mice) develop autoimmune disease with characteristics similar to the human autoimmune disease systemic erythematosus (SLE). These studies suggest that Lyn is an important severity gene in autoimmunity. The aim of this grant will be to identify Lyn-dependent signaling pathways that lead to autoimmune disease, with a major focus being on the lipid kinase pathway. We will use a combination of genetic and biochemical approaches to reveal critical genes and pathways. Cataloging the molecular changes related to alterations in Lyn activity will, we believe, provide insight into the genetic defects or signal perturbations underlying human autoimmune diseases. In this way, our study will aid in the diagnosis of human autoimmune diseases and uncover useful targets for more specific and effective treatments.Read moreRead less