Development of Oxidized LDL Receptor (CD36) Knockout Mice and Its Application to Elucidation of Molecular Mechanism for Atherogenesis

CD36是一种表达于血小板、单核/巨噬细胞和脂肪组织的膜糖蛋白。CD36属于B类清道夫受体家族。我们在1990年发现了CD36缺乏症患者，并对这些患者的病理生理学进行了分析。我们发现了CD36基因的3个新突变，并报告了CD36缺陷患者的巨噬细胞结合氧化型低密度脂蛋白的能力降低，并对泡沫细胞的形成产生了抵抗。因此，CD36可能是氧化低密度脂蛋白的重要受体之一。此外，我们还发现CD36在CD36阳性患者的心肌中也有表达，但在CD36缺陷患者的心肌中不表达，CD36缺陷可能导致这些患者发生心肌病的频率较高。我们发现CD36缺陷患者伴有胰岛素抵抗，这是多危险因素综合征的常见表型。在本研究中，我们利用基因工程技术建立了CD36基因敲除小鼠，阐明了CD36在动脉粥样硬化发病机制中的作用，并建立了嵌合体小鼠，获得了CD36基因敲除小鼠的纯合子。我们已经进行了回交育种，目前正在试图观察这些小鼠的血脂、葡萄糖代谢以及是否存在胰岛素抵抗的变化。最后，我们将研究CD36基因敲除小鼠对动脉粥样硬化的易感性。

CD36 is a membrane glycoprotein expressed on platelets, monocytes/macrophages and adipose tissues. CD36 belongs to the class B scavenger receptor family. We found patients with CD36 deficiency in 1990 and analyzed the pathophysiology of these patients.We have identified 3 novel mutations in the CD36 gene and reported that macrophages from CD36-deficient patients showed a reduced capacity to bind oxidized LDL and were resistant to foam cell formation. Thus, CD36 may be one of the important receptors for oxidized LDL. Furthermore, we have found that CD36 is also expressed in cardiac muscles of CD36-positive subjects, but not in those of CD36-deficient patients.The deficiency of CD36 may lead to the high frequency of cardiomyopathy in these patients.Little has been known as to the in vivo effect of CD36 deficiency. We found that CD36-deficient patients are accompanied by insulin resistance, which is a common phenotype of multiple risk factor syndrome. In the current study, we have used genetic engineering techniques to establish CD36 knockout mice and elucidate the role of CD36 in the pathogenesis of atherosclerosis.We have established chimera mice and have obtained homozygotes of CD36 knockout mice. We have performed a backcross breeding and are currently trying to see the changes of serum lipids, glucose metabolism and the presence or absence of insulin resistance in these mice. We will finally examine the susceptibility of CD36 knockout mice to atherosclerosis.