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Elucidation of the Molecular Mechanism of Atherosclerosis Induced by Unsaturted Lysophosphatidic Acid and Establishment of the Anti-athrosclerotic Therapy

不饱和溶血磷脂酸致动脉粥样硬化分子机制的阐明及抗动脉粥样硬化疗法的建立

基本信息

批准号：
15390246
负责人：
SHIBATA Katsushi
金额：
$ 9.54万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The molecular mechanism of atherosclerosis still remains to be elucidated. The purposes of this study are to clarify the pathological significance of unsaturated-LPA in atherosclerosis and to develop the novel therapeutic strategy for atherosclerosis. Following experiments were performed. 1,Cloning of the novel unsaturated-LPA specific receptor : We are in the final step in the following experiments ; (1)Expression cloning using unsaturated-LPA stimulated activation of the ERK and p38MAPK as a functional marker, (2)The receptor binding experiment using radiolabeled unsaturated-LPA as a ligand. 2,Identification of the atherogenic factors : Using primary culture system of vascular smooth muscle cells(VSMCs) maintaining a differentiated phenotype, we demonstrated that epiregulin was released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for the progression of atherosclerosis (Circulation. 2003 18;108:2524-9.). 3,In vivo effect of unsaturated-LPA o … More n the atherogenesis. We demonstrated that treatment of rat common carotid arteries(CCAs) with 18:1 but not 18:0 LPA potently induced neointimal formation and that the coordinated activation of the ERK and p38MAPK pathways in the CCAs was critical for the 18:1 LPA-induced vascular remodeling in vivo (Circulation.2003 108:1746-52.). 3,Elucidation of the intracellular signal transduction involved in the pathogenesis of atherosclerosis : We demonstrated that IGF-I activated a protein-tyrosine phosphatase, SHP-2 in differentiated VSMCs and that the activated SHP-2 then dephosphorylated insulin receptor substrate-1(IRS-1), resulting in blockade of the activation of the ERK and p38MAPK pathways which are critically involved in de-differentiation of VSMCs. The results indicate that the IRS-1/SHP-2 interaction acts as a switch controlling phenotypic modulation of VSMCs (J.Biol.Chem.2004 279:40807-40818.). 4,Generation of atherosclerotic mouse : We have generated the transgenic mouse over-expressing the enzyme involved in the lipid synthesis, which is expected to have a disorder in the lipid metabolism. Less

动脉粥样硬化的分子机制仍有待阐明。本研究的目的是阐明不饱和LPA在动脉粥样硬化中的病理意义，并开发动脉粥样硬化的新治疗策略。进行以下实验。1、新型不饱和LPA特异性受体的克隆：（1）以不饱和LPA激活ERK和p38 MAPK为功能标记的表达克隆，（2）以放射性标记的不饱和LPA为配体的受体结合实验。2、致动脉粥样硬化因子的鉴定：使用维持分化表型的血管平滑肌细胞（VSMCs）的原代培养系统，我们证明了表皮调节蛋白从由致动脉粥样硬化因子引发的VSMCs中释放，并且作为动脉粥样硬化进展的主要自分泌/旁分泌因子（Circulation. 2003 18;108：2524-9.）。3、不饱和-LPA的体内效应 ...更多信息在动脉粥样硬化形成中的作用。我们证明了用18：1而不是18：0 LPA处理大鼠颈总动脉（CCA）有效地诱导了新生内膜形成，并且CCA中ERK和p38 MAPK途径的协调激活对于18：1 LPA诱导的体内血管重塑是关键的（Circulation. 2003 108：1746-52.）。3、动脉粥样硬化发病机制中细胞内信号转导的研究：我们证实IGF-I在分化的VSMCs中激活蛋白酪氨酸磷酸酶SHP-2，激活的SHP-2使胰岛素受体底物1（IRS-1）去磷酸化，从而阻断ERK和p38 MAPK通路的激活，这两条通路在VSMCs的去分化中起关键作用。结果表明IRS-1/SHP-2相互作用充当控制VSMC表型调节的开关（J.Biol.Chem.2004 279：40807-40818.）。4、动脉粥样硬化小鼠的产生：我们已经产生了过表达参与脂质合成的酶的转基因小鼠，预期其具有脂质代谢障碍。少