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，以血栓形成和反复流产为特征。这种疾病的特征是循环中的抗体与血液中一种名为Beta 2-糖蛋白I的蛋白质结合，这种蛋白质被认为在控制人类和其他哺乳动物的凝血系统方面很重要。然而，为了研究这种蛋白质的功能而设计的实验已经研究了它在试管中的功能。β2-GPI在体内的确切作用尚未确定。一种观察这种蛋白质在体内功能的方法是，如果你从动物(如老鼠)中排除这种蛋白质。通过复杂的分子生物学技术，我们已经能够在小鼠身上消除Beta 2-GPI基因，从而产生不产生任何Beta 2-GPI蛋白的小鼠。这些小鼠被称为Beta 2-GPI基因敲除小鼠，是检测Beta 2-GPI功能的理想动物模型。这项提案中概述的实验将检验Beta 2-GPI在凝血、动脉粥样硬化中的作用，以及在这些动物中产生Beta 2-GPI抗体的效果。此外，由于目前对患有这些抗体的患者的治疗包括长期、有时是终生的药物治疗，这些药物稀释血液，具有潜在的副作用，我们正在研究一种新的治疗方法，旨在消除结合Beta 2-GPI的抗体。如果可以消除这些患者对Beta 2-GPI的抗体产生，就不需要终生服用肝素等稀释血液的药物，因此这些药物的问题将会减少。为了做到这一点，我们已经获得了Beta 2-GPI的一个特殊的化学修饰部分，它已经在初步实验中被证明是有效的。

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.