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    题名: 蛋白激脢CK2訊息傳遞在大腦衍生營養因子抗細胞凋亡機制中所扮演的角色及機制探討---SRF及其下游基因Mcl-1表現的影響
    其它题名: Role and Mechanism of Ck2 Signaling Involved in the Anti-Apoptotic Action of Brain-Derived Neurotrophic Factor (BDNF)---Role of Serum Response Factor (SRF) and Its Downstream Gene Mcl-1 Expression
    作者: 趙知章
    贡献者: 國立政治大學生命科學研究所
    行政院國家科學委員會
    关键词: 基礎醫學;神經營養因子;神經系統;大腦衍生營養因子
    日期: 2008
    上传时间: 2012-11-15 11:23:42 (UTC+8)
    摘要: 神經營養因子在神經系統中所參與之提升神經細胞的存活和再生的功能一直是一個重要的研究課題，其中以neurotrophin 類的神經營養因子被研究地較為詳盡。大腦衍生營養因子（brain-derived neurotrophic factor，簡稱BDNF）是被歸類於neurotrophin family 中的一種神經營養因子，過去研究報告指出，BDNF 處理可以減少神經細胞的退化和死亡，亦可延緩因遺傳性缺陷所引發之神經細胞退化現象，這些研究結果說明了BDNF 對於促進神經細胞的存活有相當的重要性。細胞凋亡（apoptosis）是普遍存在於退化性神經病變過程中的一種病理現象，截至目前為止，已有不少的研究報告探討BDNF 所調控的訊息傳遞路徑如何參與神經細胞抗凋亡的機制（anti-apoptotic mechanism），其中 PI3-Kinase 的訊息傳遞路徑已被證實會參與在抗細胞凋亡機制中。除此之外，近年來蛋白激.CK2（protein kinase CK2）也被證實參與在細胞抗凋亡機制中。這些研究報告指出，CK2 可以經由活化Akt/PKB、NF-κB 和ARC 蛋白（apoptosis repressor with caspase recruitment domain）等機制來促進細胞的存活，臨床診斷髮現在阿茲海默症和精神分裂症之病患腦部的CK2蛋白質含量和活性皆較正常人為低。另一方面，雖然轉錄分子serum response factor（SRF）參與調節細胞的增生與分化，但研究細胞凋亡的相關文獻指出，活化的caspase 會對SRF 進行切割進而抑制其對c-fos 基因的轉錄能力使細胞趨向凋亡途徑；基因突變的研究結果也顯示SRF 喪失功能會伴隨抗細胞凋亡相關蛋白Bcl-2 表現量的減少以及細胞凋亡現象的發生；除此之外，SRF/Elk-1 complex 亦被證實參與促進Bcl-2 相關蛋白Mcl-1 基因表現的作用。因此，本研究計畫擬探討CK2 參與BDNF 抗細胞凋亡的神經保護機制以及在此過程中CK2 對調控SRF 及抗細胞凋亡蛋白Mcl-1 的相關機制。本計畫擬定兩年執行完成，各年計畫目的如下：第一年的主要目的是（1）在活體實驗大鼠海馬迴腦部確立BDNF-CK2-SRF- Mcl-1 訊息傳遞路徑的相關性，以及（2）在海馬迴腦部調控CK2 或SRF 活性是否會拮抗BDNF 對Mcl-1 基因表現的影響。第二年的主要目的則是（1）利用PC12 細胞株實驗確定CK2 會藉由磷酸化SRF 而促進其對 DNA binding 能力，以及（2）探討CK2 磷酸化SRF 是否會促進Mcl-1 基因啟動子的活性。
    Among various neurotrophic factors, the neurotrophins are well studied regarding their roles in neuronal survival and neural regeneration. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is considered as an important neurotrophic factor to protect against neuronal degeneration and neuronal death. In addition, BDNF administration also attenuates neural degeneration from genetic-inherited deficient mice. Apoptosis is one of the pathological events occurs during the process of neural degeneration. Up to now, there are many studies focusing on the role of the BDNF signaling pathway involved in anti-apoptosis. It has been shown that the PI-3 kinase pathway is an important pathway involved in the anti-apoptotic effect of neurotrophic factors. Recently, protein kinase CK2 was also found to be involved in the mechanism of anti-apoptosis. There are many reports showing that protein kinase CK2 could activate protein kinase Akt/PKB, NF-κB and ARC protein (apoptosis repressor with caspase recruitment domain) and to enhance cell survival. Studies have also revealed that both CK2 activity and CK2 concentration were decreased in the cortex of Alzheimer』s disease patients and schizophrenic patients. Meanwhile, the transcription factor serum response factor (SRF) was found to be cleaved by activated caspase during the induction of apoptosis. Conditional down-regulation of the SRF gene was shown to down-regulate the expression of bcl-2. In addition, down-regulation of Mcl-1 gene expression by Elk-1 mutation was found to be mediated through an SRF-dependent mechanism. Based on these observations, the present study is aimed to investigate the role and mechanism of CK2 signaling involved in the anti-apoptotic action of BDNF by using molecular, cellular, biochemical and physiological approaches. The specific aims of the present study for the first year are as follows: (1) to investigate the relationships among CK2, SRF and Mcl-1 in rat hippocampal under BDNF treatment; (2) to examine whether manipulations of CK2 and SRF activity alter the effect of BDNF on Mcl-1 gene expression. The specific aims for the second year study are as follows: (1) to examine whether CK2 phosphorylation of SRF promotes the DNA-binding activity of SRF in PC12 cells; (2) to investigate whether CK2 enhances the promoter activity of Mcl-1 through phosphorylation of SRF in PC12 cells.
    關聯: 基礎研究
    學術補助
    研究期間:9708~ 9807
    研究經費: 1045仟元
    数据类型: report
    显示于类别:[神經科學研究所] 國科會研究計畫

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