Molecular analysis and clinical application of LR11 in SMCs.

本研究的目的是阐明LR11基因在动脉粥样硬化发生发展中的分子机制。LR11基因敲除小鼠的建立及鉴定。LR11-/-小鼠的出生和生长特性与LR11/小鼠无明显差异。LR11-/-小鼠袖带损伤后内膜厚度明显低于LR11/小鼠。培养的LR11-/-SMC在PDGF-BB刺激下的迁移活性明显低于LR11/SMC，2.通过膜跨区和胞内区的缺失，建立了LR11A分泌可溶性LR11的功能分析。除显示SMCs的迁移活性外，可溶性形式还具有诱导巨噬细胞迁移、附着和脂质掺入的活性。LR11基因在SMC中的调控：PDGF-BB可显著促进LR11基因的转录，而匹伐他汀可抑制LR11基因转录的上调。LR11过表达的SMC对匹伐他汀的迁移反应减弱，这些结果表明在研究年限内几乎可以完成研究的目的。

The aim of study is to clarify the molecular mechanism of LR11, a gene specifically expressed in intimal SMCs, in the development of atherosclerosis.1. Establishment and characterization of LR11 knockout mice.The exon 1 of LR11 gene was replaced by NEO gene. The birth and growth properties of LR11-/- mice did not show any obvious difference from those of LR11+/+ mice. The intimal thickness after cuff injury in LR11-/- mice was significantly reduced compared with that in LR11+/+ mice. The cultured LR11-/- SMCs showed a significant decrease in migration activity under PDGF-BB stimulation compared with the LR11+/+ SMCs,2. The functional analyses of secreted soluble form of LR11A secreted soluble form of LR11 was established by the deletion of membrane-spanning and intracellular regions. The soluble form showed the inducing activity for migration, attachment and lipd incorporation of cultured macrophages, in addition to the migration activity of SMCs.3. Regulation of LR11 gene in SMCs.The LR11 gene transcription was significantly increased by PDGF-BB, and the increased transcription was inhibited by the treatment of pitavastatin. The LR11-overexpressing SMCs showed the decreased response to pitavastatin for migration activity.These results show that the aim of study could be almost completed in the study years.