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Title: 经典型瞬时受体电势(TRPC)通道与脑缺血
Author: 杜婉璐
Degree Level: 博士
Issued Date: 2009-05-22
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 王以政
Keyword: 脑缺血 ; 经典型瞬时受体电势通道
Alternative Title: Proteolytic degradation of TRPC6 contributes to ischemic neuronal death
Major: 神经生物学
Abstract: 脑缺血后的诸多病理过程最终会导致严重的脑损伤,比如谷氨酸兴奋毒作用,炎症作用以及细胞凋亡的作用等等。然而,针对这些破坏性的病理过程所开发研制的药物(旨在干扰这些破坏性通路的启动或进行)却在临床治疗应用方面不尽如人意。因此,我们提出,神经元内在的保护性通路也许对于降低缺血性损伤非常重要。这里,我们的研究论文报道经典型瞬时受体电势通道(canonical transient receptor potential channel, 简称TRPC通道)家族中的TRPC6蛋白是神经元中介导神经细胞保护通路的一个重要分子。在大鼠脑缺血模型中,我们发现皮层的TRPC6蛋白水平有显著的下降,而其他TRPC蛋白水平并未有明显降低,并且这一现象发生在神经元中而不是胶质细胞中。在细胞缺血模型中(oxygen-glucose deprivation, 简称OGD),我们证实了TRPC6蛋白的神经元保护作用是依赖于下游CREB的激活。此外我们的结果表明,缺血过程中,NMDA受体的开放介导了下游calpain的激活,进而导致TRPC6蛋白的降解,从而促进了缺血性神经元死亡。提高TRPC6在脑中的蛋白表达量(构建转基因小鼠)或者特异的阻断calpain降解TRPC6(侧脑室注入带有calpain切割位点的TRPC6肽段),这两种策略对于缺血引起的脑损伤都有很好的保护作用。因此,我们认为TRPC6通道蛋白作为一个新的靶点可能会为脑缺血治疗带来新的希望。
English Abstract: Brain injury after focal cerebral ischemia develops from a series of pathological processes, including excitotoxicity, inflammation and apoptosis. However, the results of clinical trials to prevent ischemic brain damage by blocking the detrimental effects are disappointing. Preservation of survival might be also important for treatment of ischemia. Here, we report that proteolytic degradation of the transient receptor potential canonical (TRPC) 6 contributes to ischemic brain damage. The TRPC6 protein level in the neurons was greatly reduced in ischemia. This downregulation was specific for TRPC6 in the members of TRPC subfamily, prior to neuronal death and mediated by the N-methyl-D-aspartate receptor (NMDAR)-dependent calpain proteolysis. A fusion peptide derived from the calpain cleavage site of TRPC6 markedly inhibited calpain-mediated its degradation and protected rat brains from ischemic damage. In transgenic mice overexpressing TRPC6 in the forebrain neurons, the activity of cAMP-response element binding protein (CREB) was enhanced and the infarct volume was greatly reduced. Together, these results suggest that calpain-mediated downregulation of TRPC6 contributes to ischemic cell death and that suppression of its degradation protects neurons from ischemic damage.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2409
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
经典型瞬时受体电势(TRPC)通道与脑缺血.杜婉璐[d].中国科学院上海生命科学研究院,2009.20-25
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