Characterisation of an in-vivo thrombosis animal model of the antiphospholipid syndrome using Beta 2-GPI KO mice

抗磷脂综合征是一种自身免疫性疾病，以血栓形成和复发性流产为特征。这种疾病的特点是循环抗体结合血液中的一种叫做β 2-糖蛋白i的蛋白质，这种蛋白质被认为对控制人类和其他哺乳动物的凝血系统很重要。然而，旨在研究这种蛋白质功能的实验已经在试管中研究了它的功能。β 2-GPI在体内的确切作用尚未确定。观察这种蛋白质在体内功能的一种方法是，如果你从动物体内剔除这种蛋白质，比如老鼠。通过复杂的分子生物学技术，我们已经能够消除小鼠体内的β 2-GPI基因，从而获得不产生任何β 2-GPI蛋白的小鼠。这些小鼠被称为β 2-GPI敲除小鼠，是研究β 2-GPI功能的理想动物模型。本提案中概述的实验将检验β 2-GPI在这些动物凝血、动脉粥样硬化中的作用以及β 2-GPI抗体产生的影响。此外，由于目前对患有这些抗体的患者的治疗包括长期，有时是终身，使用药物稀释血液，这有潜在的副作用，我们正在研究一种新的治疗方法，旨在消除结合β 2-GPI的抗体。如果可以消除这些患者产生的β 2-GPI抗体，就不需要终身服用肝素等药物，因为肝素会稀释血液，因此这些药物的问题就会减少。为了做到这一点，我们已经获得了β 2-GPI的专门化学修饰部分，已经在初步实验中证明了它的作用。

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.