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Title: Lipid Rafts介导Nogo66信号转导机制的研究
Author: 于伟英
Degree Level: 博士
Issued Date: 2005
Degree Grantor: 中国科学院神经科学研究所
Place of Degree Grantor: 中国科学院神经科学研究所
Supervisor: 冯林音
Keyword: Nogo66受体 ; 神经突起生长的抑制 ; 信号转导
Alternative Title: Role of Lipid Rafts in Nogo66 Induced Inhibition of Neurite Outgrowth
Abstract: NogoA是一类主要位于中枢字中经系统髓鞘膜上的神经突起生长抑制因子。N09066是NogoA中的一个活性区域,它通过与细胞表面的NgR结合,同时或继而与p75和LINGO-1相互.作用,激活下游的RhoA而传递抑制性的信号,但目前.有关Nogo66信号传递的具体机制仍有许多不清楚之处,值得进一步研究。本文中我们发现NgR和p75在前脑、小脑和培养的小脑颗粒细胞Lipid Rafts中都有共定位,并且两者在Lipid Rafts上可相互作用。p75在Lipid Rafts的分布随发育进程而受调控,在成熟大鼠大脑LilnidRafts中的量明显高于生后8天大鼠大脑Lipid Rafts中的量。灿。A也可分布于成年大鼠大脑、小脑月项粒细胞以及皮质神经元的Lipid Rafts上。应用一种胆固醇合成酶的抑制剂lovastatill处理小脑颗粒细胞,可部分阻止Nogo"所引起的对神经突起生长的抑制作用,其机制可能是lovastatin刀戍少了孙oA在Lipid Rafts上的定位,从而阻止了Nogo66信号的传递。研究还证明,仔一甲基环状糊精可抑制NgR和p75在小脑颗粒细胞Lipid Rafts中的定位,并且抑制Nogo66引起的RhoA活性。此外,在PC12细胞中,p75可受Nogo66的调节而增加其在Lipid Rafts中的定位。所有这些结果都表明,Lipid Rafts是Nogo66信号转导过程中一个必不可少的信息平台,对其下游信号的传递起着非常重要的作用。
English Abstract: NogoA is a myelin-associated component that inhibits neurite outgrowth. Nogo66, a portion of NogoA, binds to Nogo66 receptor (NgR) and transduce the inhibitory signaling. The signal transduction of NgR requires LINGO-1 and p75, the low-affinity nerve growth factor receptor. However, Nogo signaling mechanism is poorly understood. Here we -observed that NgR and p75 were partitioned in low-density membrane raft fractions in forebrains, cerebella and cerebellar grannie cells. NgR interacted with p75 in lipid rafts. Localisation of p75 in lipid rafts was developmentally regulated. The portion of p75 in lipid rafts was much larger in adult rat brain than that in P8 brain. RhoA was also located in the lipid rafts of brain and cerebellar granule cells as well as cortical neurons. Treatment with lovastatin, an inhibitor of cholesterol biosynthesis, attenuated the Nogo66-induced inhibition of neurite outgrowth of cerebellar granule cells probably by decreasing the localization of RhoA in the lipid rafts and hence'blocking the Nogo66 signaling. In the further studies, we observed that disruption of lipid rafts by beta-methylcyclodextrin significantly reduced the localizaton of NgR and p75 in the lipid rafts as well as blocked the Nogo66 induced RhoA activation. In addition, we demonstrated that p75 was recruited into the lipid rafts by Nogo66 stimulation in PC 12 cells, Our results suggest'an important role of lipid rafts in facilitating the interaction between Nogo66 receptors and provide insight into mechanisms underlying the inhibition of neurite outgrowth by NogoA.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2253
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
Lipid Rafts介导Nogo66信号转导机制的研究.于伟英[d].中国科学院神经科学研究所,2005.20-25
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