Elucidation of C-reactive proteins in atherosclerosis

阐明动脉粥样硬化中的 C 反应蛋白

• 批准号: 16390089
• 负责人: FAN Jianglin
• 金额: $ 9.22万
• 依托单位: University of Yamanashi (2006)University of Tsukuba (2004-2005)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390089/
• 关键词: Transgenic rabbits; CRP; Atherosclerosis; Hypercholesterolemia; Macrophages; Plaque; Animal model; Inflammation; C-反応蛋白; 遺伝子改変; 動物モデル; 脂質代謝; 遺伝子導入; CRP

In this project, we have performed two studies in order to elucidate the functional roles of CRP in atherosclerosis. In the initial study, we used both human and rabbit specimens in attempt to clarify (1) whether CRP is present in the lesions, (2) if so, where CRP is deposited, (3) whether vascular cells especially macrophages can synthesize CRP. Our study showed that CRP is ubiquitously present in the lesions regardless of the lesion stage. CRP is closely associated with apoB but not macrophages. Using both Northern blotting and real-time RT-PCR, we demonstrated that CRP mRNA is basically expressed in the liver but rarely, if any, by macrophages. We also demonstrated that in hypercholesterolemic rabbits, the aortic lesion size is positively correlated with the levels of plasma CRP. In order to demonstrate whether CRP is directly involved in the lesion formation, we also generate transgenic rabbits expressing human CRP in the liver. For this study, we used a liver-specific expression construct along with insulators and established three independent lines of CRP transgenic rabbits. Now, we are using these CRP transgenic rabbits to perform atherosclerosis study. We also obtained CRP inhibitors from ISIS company and hope to investigate whether inhibition of CRP can prevent atherosclerosis.

在这个项目中，我们进行了两项研究来阐明CRP在动脉粥样硬化中的功能作用。在最初的研究中，我们使用人类和兔子标本试图澄清(1)病变中是否存在CRP，(2)如果存在，CRP沉积在哪里，(3)血管细胞特别是巨噬细胞是否可以合成CRP。我们的研究表明，无论病变处于何种阶段，CRP都普遍存在于病变中。CRP与载脂蛋白b密切相关，但与巨噬细胞无关。通过Northern blotting和real-time RT-PCR，我们发现CRP mRNA基本在肝脏中表达，但很少在巨噬细胞中表达。我们还证明，在高胆固醇血症的家兔中，主动脉病变大小与血浆CRP水平呈正相关。为了证明CRP是否直接参与病变的形成，我们还在肝脏中产生了表达人CRP的转基因家兔。在这项研究中，我们使用了肝脏特异性表达构建体和绝缘子，并建立了三个独立的CRP转基因家兔系。现在，我们正在使用这些CRP转基因家兔进行动脉粥样硬化研究。我们还从ISIS公司获得了CRP抑制剂，希望研究抑制CRP是否可以预防动脉粥样硬化。

项目成果

Macrophage-derived lipoprotein lipase increases aortic atherosclerosis in cholesterol-fed Tg rabbits

• DOI: 10.1016/j.atherosclerosis.2004.10.044
• 发表时间: 2005-03-01
• 期刊: ATHEROSCLEROSIS
• 影响因子: 5.3
• 作者: Ichikawa, T;Liang, JY;Fan, JL
• 通讯作者: Fan, JL

Lp(a) enhances coronary atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits

• DOI: 10.1016/j.atherosclerosis.2006.08.056
• 发表时间: 2007-08-01
• 期刊: ATHEROSCLEROSIS
• 影响因子: 5.3
• 作者: Kitajima, Shuji;Jin, Yingji;Fan, Jianglin
• 通讯作者: Fan, Jianglin

Increased expression of VEGF in kidney leads to progressive impairment of gomerular functions in transgenic rabbits.

肾脏中 VEGF 表达的增加导致转基因兔的肾小球功能逐渐受损。

• 发表时间: 2007
• 期刊: J Am Soc Nephrol (In press)
• 作者: Liu;E.;Morimoto;M.;Kitajima;S.;Yu;Y.;Koike;T.;Shiiki;H.;Nagata;M.;Watanabe;T.;Fan;J.
• 通讯作者: J.

High lipoprotein lipase increases insulin sensitivity in transgenic rabbits.

高脂蛋白脂肪酶增加转基因兔子的胰岛素敏感性。

• 发表时间: 2005
• 期刊: Metabolism 54
• 作者: Liu E;et al. (Last)
• 通讯作者: et al. (Last)

Establishment of a SPF colony of human apo(a) transgenic rabbits by frozen-thawed embryo transfer.

通过冻融胚胎移植建立人 apo(a) 转基因兔 SPF 群体。

• 发表时间: 2005
• 期刊: Exp. Anim 54
• 作者: Watanabe;N. et al.
• 通讯作者: N. et al.