Molecular analysis and clinical application of LR11 in SMCs.

本研究的目的是阐明LR11在动脉粥样硬化发生中的分子机制，LR11是一种在内膜SMCs中特异性表达的基因。LR11基因敲除小鼠的建立与表征。LR11基因外显子1被NEO基因取代。LR11-/-小鼠的出生和生长特性与LR11+/+小鼠无明显差异。与LR11+/+小鼠相比，LR11-/-小鼠袖带损伤后的内膜厚度明显减少。与LR11+/+ SMCs相比，培养的LR11-/- SMCs在PDGF-BB刺激下的迁移活性显著降低，2。通过缺失跨膜区和胞内区，确定了LR11的分泌可溶性形式。可溶性形式除具有smcs的迁移活性外，还具有诱导培养巨噬细胞迁移、附着和脂质结合的活性。LR11基因在SMCs中的调控作用。PDGF-BB可显著增加LR11基因转录，而匹伐他汀可抑制LR11基因转录的增加。过表达lr11的SMCs对匹伐他汀的迁移活性反应减弱。这些结果表明，在研究年限内，研究目标基本可以完成。

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.