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Establishment of A New Strategy for the Treatment of Atherosclerosis by Inhibition of an Oxidized LDL Receptor, CD36

通过抑制氧化LDL受体CD36建立治疗动脉粥样硬化的新策略

基本信息

批准号：
11557055
负责人：
YAMASHITA Shizuya
金额：
$ 8.64万
依托单位：
Osaka University Graduate School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

CD36 is an 88 kDa membrane glycoprotein and is expressed on platelets, monocytes, monocyte-derived macrophages and adipose tissues. CD36 was reported to be a receptor for collagen and thrombospondin as well as a transporter of long-chain fatty acids. We have identified patients with CD36 deficiency and reported 3 novel mutations in the CD36 gene. We also found that CD36 is a receptor for oxidized LDL, using monocyte-derived macrophages from CD36-deficient subjects and that CD36 is expressed on foamed macrophages in the human atherosclerotic aorta and coronary arteries. In the current study, we tried to establish polyclonal antibodies that block CD36 and also to develop CD36 knockout mice by genetic engineering technique. We have obtained ES cells with a homologous recombination and are currently trying to obtain chimera mice by microinjection to examine the effect of CD36 knockout on the development of atherosclerosis in apo E or LDL receptor knockout mice. We have so far identified 26 CD36-deficient subjects, all of whom showed a complete deficiency of myocardial uptake of ^<123>I-BMIPP, a long-chain fatty acid analogue. It is noteworthy that the CD36-deficient patients were accompanied by hyperlipidemia (especially hypertriglyceridemia), an increase in remnant lipoproteins and a slight elevation of blood pressure. These subjects were also accompanied by insulin resistance and multiple risk factors. Thus, deficiency of CD36 may be one of the genetic causes of multiple risk factor syndrome possibly through insulin resistance. The mechanism for the insulin resistance in patients with CD36 deficency is currently underway.

CD36是一种88 kDa的膜糖蛋白，在血小板、单核细胞、单核细胞衍生的巨噬细胞和脂肪组织上表达。据报道，CD36是胶原蛋白和血小板反应蛋白的受体以及长链脂肪酸的转运蛋白。我们发现了CD36缺乏症患者，并报告了3个CD36基因的新突变。我们还发现，CD36是氧化LDL的受体，使用来自CD36缺陷受试者的单核细胞衍生的巨噬细胞，并且CD36在人动脉粥样硬化主动脉和冠状动脉中的泡沫巨噬细胞上表达。本研究试图建立CD36的多克隆抗体，并利用基因工程技术建立CD36基因敲除小鼠。我们已经获得了具有同源重组的ES细胞，并且目前正在尝试通过显微注射获得嵌合体小鼠，以检查CD36敲除对apo E或LDL受体敲除小鼠中动脉粥样硬化发展的影响。到目前为止，我们已经确定了26名CD 36缺陷的受试者，他们都表现出心肌摄取长链脂肪酸类似物-<123>值得注意的是，CD36缺陷型患者伴有高脂血症（尤其是高甘油三酯血症）、残余脂蛋白增加和血压轻度升高。这些受试者还伴有胰岛素抵抗和多种危险因素。因此，CD36的缺乏可能是多危险因素综合征的遗传原因之一，可能通过胰岛素抵抗。CD36缺乏患者胰岛素抵抗的机制目前正在研究中。