Antiphospholipid Syndrome Related Thrombosis: Understanding The Disease Pathogenic Mechanisms Is The Key To Better Diagnosis And Treatment
Funder
National Health and Medical Research Council
Funding Amount
$607,497.00
Summary
Patients with the Antiphospholipid Syndrome develop thrombosis at a young age. It requires long-term treatment with blood thinning medications, which have risks of severe bleeding. Methods are needed to decide which patients require long term treatment, avoiding unnecessary treatment in low risk patients. Such methods do not currently exist. In this study we explore how useful two novel assays developed by us are in identifying which of these patients are at high risk of thrombosis.
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.
The mechanisms controlling cell growth are often disrupted in cancers. We have identified on such growth control mechanism. When normal body cells are treated with a particular family of drugs known as histone deacetylase inhibitors, they react by stopping proliferating, but will resume normal growth when the drug is removed. However, we have found that similarly treated tumour cells are killed by these drugs. The difference between the normal and tumour cells is the functionality of a particula ....The mechanisms controlling cell growth are often disrupted in cancers. We have identified on such growth control mechanism. When normal body cells are treated with a particular family of drugs known as histone deacetylase inhibitors, they react by stopping proliferating, but will resume normal growth when the drug is removed. However, we have found that similarly treated tumour cells are killed by these drugs. The difference between the normal and tumour cells is the functionality of a particular growth control. The identification of how this growth control mechanism operates in normal cells, and defining the defect in tumour cells has the potential to identify new targets for more specific and potent anti-cancer drugs. The increased specificity, i.e. destruction of only the tumour cells while have little or no effect on the surround normal body tissue, would be extremely beneficial as one of the drawbacks to conventional anti-cancer treatments is their unwanted normal tissue toxicities. This is cause of the many debilitating side effects associated with chemo and radiotherapy which can limit the clinical effectiveness of these treatments.Read moreRead less
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
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.
Characterisation Of An In-vivo Thrombosis Animal Model Of The Antiphospholipid Syndrome Using Beta 2-GPI KO Mice
Funder
National Health and Medical Research Council
Funding Amount
$467,310.00
Summary
The antiphospholipid syndrome is an autoimmune condition characterised by the presence of thrombosis and recurrent miscarriage. The disorder is characterised by circulating antibodies which bind a protein in the blood known as Beta 2- Glycoprotein I. This protein has been thought to be important in controlling the clotting system in humans and other mammals. However, the experiments that have been designed to look at the function of this protein have looked at its function in the test tube. The ....The antiphospholipid syndrome is an autoimmune condition characterised by the presence of thrombosis and recurrent miscarriage. The disorder is characterised by circulating antibodies which bind a protein in the blood known as Beta 2- Glycoprotein I. This protein has been thought to be important in controlling the clotting system in humans and other mammals. However, the experiments that have been designed to look at the function of this protein have looked at its function in the test tube. The exact role of Beta 2-GPI in the body, has not been determined. A way of looking at the function of this protein in the body would be if you eliminated the protein from an animal such as a mouse. By sophisticated molecular biology techniques 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 are an ideal animal model to examine the function of Beta 2-GPI. Experiments outlined in this proposal will examine the role of Beta 2-GPI in clotting, atherosclerosis and the effect of production of antibodies to Beta 2-GPI in these animals. In addition, since current treatment of patients that have these antibodies consists of long term, sometimes lifelong, treatment with drugs that thin the blood which have potential side effects, we are investigating a novel treatment approach which is directed at eliminating the antibodies that bind Beta 2-GPI. If one could eliminate the antibody production to Beta 2-GPI by these patients there would not be a need for lifelong treatment with drugs such as heparin which thins the blood and there would thus be a reduction in the problems with these medications. To do this we have obtained a specialised chemically modified portion of Beta 2-GPI that has already been shown to work in preliminary experiments.Read moreRead less