【摘要】：第一部分O-OlcNAc糖基化對Insulin-PI3K-AKT信號通路的調(diào)節(jié) 目的： 在不同細(xì)胞中研究O-GlcNAc糖基化對Insulin-PI3K-AKT信號通路的影響。 方法： 在HEK-293FT, HepG2, N2a細(xì)胞和原代培養(yǎng)的小鼠海馬神經(jīng)元過表達(dá)或下調(diào)O-GlcNAc糖基轉(zhuǎn)移酶OGT,或使用調(diào)節(jié)O-GlcNAc糖基化修飾關(guān)鍵酶的抑制劑處理細(xì)胞,改變細(xì)胞內(nèi)O-GlcNAc糖基化水平。利用免疫共沉淀的方法研究Insulin-PI3K-AKT信號通路中可以被O-GlcNAc糖基化的組成部分。采用蛋白免疫印跡技術(shù)分析不同細(xì)胞內(nèi)O-GlcNAc糖基化對AKT和GSK-3β磷酸化和活性的影響。 結(jié)果： 1)在HEK-293FT細(xì)胞中,免疫共沉淀和蛋白免疫印跡分析顯示,AKT和GSK-3β是Insulin-PI3K-AKT信號通路中受O-GlcNAc糖基化修飾的蛋白。 2)在不同培養(yǎng)條件下,改變HEK-293FT細(xì)胞的O-GlcNAc糖基化水平,影響PI3K-AKT信號通路。O-GlcNAc糖基化負(fù)性調(diào)控AKT的Thr308和Ser473磷酸化水平,改變其活性。降低細(xì)胞內(nèi)O-GlcNAc糖基化,下調(diào)GSK-3β的Ser9的磷酸化,但升高細(xì)胞內(nèi)的O-GlcNAc糖基化對GSK-3β的Ser9磷酸化沒有影響 3)在不同培養(yǎng)條件下,改變HepG2細(xì)胞的O-GlcNAc糖基化水平,對AKT的GSK-3β的磷酸化沒有明顯的影響。 4)N2a細(xì)胞和原代培養(yǎng)的小鼠海馬神經(jīng)元,O-GlcNAc糖基化調(diào)節(jié)AKT的磷酸化,但對GSK-3β的磷酸化沒有影響。 結(jié)論： 本研究顯示O-GlcNAc糖基化對AKT和GSK-3β的調(diào)節(jié)具有蛋白特異性和細(xì)胞特異性。Insulin-PI3K-AKT在不同的器官、組織和細(xì)胞中,扮演著不同的角色,O-GlcNAc糖基化的調(diào)節(jié)也存在著不同的表現(xiàn),在神經(jīng)元細(xì)胞內(nèi),O-GlcNAc糖基化調(diào)節(jié)AKT的活性。 第二部分O-GlcNAc糖基化在腦缺血中對細(xì)胞凋亡的影響 目的： 研究O-GlcNAc糖基化是否及如何引起細(xì)胞凋亡,探討腦缺血早期升高的O-GlcNAc糖基化對細(xì)胞凋亡的影響。 方法： 蛋白質(zhì)免疫印跡和組織免疫熒光染色分析小鼠大腦中動脈阻斷(Middle Cerebral Artery Occlusion, MCAO)腦缺血模型不同時(shí)間O-GlcNAc糖基化改變和AKT的磷酸化水平。Caspase3的活性測定和Tunel測定檢測小鼠腦缺血早期海馬細(xì)胞發(fā)生凋亡情況。在培養(yǎng)的HEK-293FT細(xì)胞,過表達(dá)OGT或者shOGT下調(diào)OGT表達(dá)以改變細(xì)胞內(nèi)O-GlcNAc糖基化水平,用MTT檢測細(xì)胞活力,熒光染色觀察細(xì)胞核的形態(tài),AnnexinV/PI流式細(xì)胞儀檢測凋亡細(xì)胞,蛋白質(zhì)免疫印跡分析早期凋亡標(biāo)志Caspase3的活化和PAPR的水解。利用免疫沉淀,定點(diǎn)突變,蛋白免疫印跡分析O-GlcNAc糖基化對AKT的影響,探討O-GlcNAc糖基化是否通過調(diào)節(jié)AKT影響細(xì)胞凋亡。 結(jié)果： 1)蛋白質(zhì)免疫印跡和組織免疫熒光染色結(jié)果顯示,小鼠MCAO模型腦缺血早期海馬組織O-GlcNAc糖基化升高,Caspase3活性增加,Tunel染色出現(xiàn)凋亡細(xì)胞。 2) HEK293FT細(xì)胞內(nèi)過表達(dá)OGT,細(xì)胞活力下降,細(xì)胞核濃縮,斷裂,呈現(xiàn)凋亡樣改變,流式細(xì)胞儀檢測到更多的凋亡細(xì)胞,蛋白免疫印跡分析結(jié)果顯示過上調(diào)細(xì)胞內(nèi)O-GlcNAc糖基化,Caspase3激活,PARP蛋白被水解。 3)AKT的Thr308和Ser473受O-GlcNAc糖基化修飾。過表達(dá)OGT升高O-GlcNAc糖基化,促進(jìn)AKT的糖基化,下調(diào)AKT的活性,引起下游底物Bad磷酸化下降,進(jìn)而活化Caspase3而引起細(xì)胞凋亡：過表達(dá)AKT,可以改善過表達(dá)OGT引起的細(xì)胞凋亡,但過表達(dá)AKT的突變體,則不能逆轉(zhuǎn)OGT引起的細(xì)胞凋亡。 4)缺血海馬的O-GlcNAc糖基化水平和AKT磷酸化水平呈負(fù)相關(guān)。免疫沉淀AKT,缺血側(cè)海馬AKT的O-GlcNAc糖基化要比對照側(cè)高。 結(jié)論： AKT的Thr308和Ser473受磷酸化和糖基化雙重修飾。在腦缺血的早期,由于應(yīng)激反應(yīng),細(xì)胞內(nèi)的O-GlcNAc糖基化增加,而使AKT的磷酸化及活性下降,磷酸化的BAD減少,經(jīng)過系列反應(yīng),進(jìn)而激活Caspase3,啟動凋亡發(fā)生。因此,O-GlcNAc糖基化在腦缺血早期的細(xì)胞凋亡中可能起重要作用。 第三部分阿爾茨海默病患者腦內(nèi)F調(diào)的O-GlcNAc糖基化影響FOXO1介導(dǎo)的自噬和Tau病變 目的： 研究O-GlcNAc糖基化對轉(zhuǎn)錄因子FoxO1的功能進(jìn)行調(diào)節(jié),探討阿爾茨海默病患者腦內(nèi)下調(diào)的O-GlcNAc糖基化對FoxO1介導(dǎo)的tau病變的影響。 方法： 在HEK-293FT細(xì)胞過表達(dá)OGT或者shOGT下調(diào)OGT的表達(dá),蛋白質(zhì)免疫印跡技術(shù)檢測O-GlcNAc糖基化對FoxO1的影響。利用蛋白合成和降解的抑制劑處理細(xì)胞,蛋白質(zhì)免疫印跡和實(shí)時(shí)定量PCR研究O-GlcNAc糖基化調(diào)節(jié)FoxO1蛋白水平的途徑。利用免疫沉淀技術(shù)研究FoxO1是否被O-GlcNAc糖基化修飾,及如何影響自身的降解。蛋白免疫印跡分析細(xì)胞核和細(xì)胞質(zhì)中FoxO1,研究O-GlcNAc糖基化改變是否影響FoxO1的細(xì)胞分布。改變細(xì)胞內(nèi)O-GlcNAc糖基化水平,檢測FoxO1報(bào)告基因的熒光素酶活性,實(shí)時(shí)定量PCR檢測FoxO1靶基因的表達(dá),蛋白免疫印跡檢測FoxO1對自噬的影響,研究O-GlcNAc糖基化改變是否影響FoxO1的活性。利用前腦神經(jīng)元特異性敲除OGT小鼠,蛋白免疫印跡技術(shù)檢測O-GlcNAc糖基化改變,AKT和foxO1的蛋白和磷酸化水平,以及自噬和蛋白酶體相關(guān)蛋白的水平,One trail物體識別,Morris水迷宮,Reversal Morris水迷宮檢測OGT KO小鼠學(xué)習(xí)記憶功能變化。蛋白免疫印跡和免疫熒光染色分析AD患者腦內(nèi)O-GlcNAc糖基化和FoxO1的蛋白水平,自噬相關(guān)蛋白水平,以及Tau的聚積。 結(jié)果： 1)改變HEK-293FT細(xì)胞的O-GlcNAc糖基化,不僅通過調(diào)節(jié)AKT的活性,而影響FoxO1蛋白的磷酸化水平,還改變FoxO1的蛋白水平。 2)升高的O-GlcNAc糖基化抑制FoxO1經(jīng)過泛素一蛋白酶體通路進(jìn)行降解。 3) FoxO1本身可以被O-GlcNAc糖基化修飾,當(dāng)O-GlcNAc糖基化修飾增加后,自身的泛素化減少,經(jīng)泛素—蛋白酶體途徑的降解受到抑制。 4) FoxO1的O-GlcNAc糖基化使得其轉(zhuǎn)錄活性增加,所調(diào)控的自噬功能增強(qiáng),但不影響其細(xì)胞內(nèi)分布。 5)前腦神經(jīng)元特異性敲除OGT的小鼠,O-GlcNAc糖基化和FoxO1水平均下降,其自噬功能下調(diào)。短時(shí)程和場景記憶能力下降。 6)AD患者腦內(nèi)O-GlcNAc糖基化水平、FoxO1的蛋白水平、P62蛋白水平的增加和LC3的下降提示自噬能力降低,AD腦內(nèi),FoxO1的蛋白水平與Tau聚積呈負(fù)相關(guān)。 結(jié)論： 轉(zhuǎn)錄因子FoxO1受O-GlcNAc糖基化修飾,增強(qiáng)其穩(wěn)定性,在AD腦中,降低的O-GlcNAc糖基化水平,使FoxO1的穩(wěn)定性下降而降解,受它調(diào)控的自噬功能下調(diào),而使磷酸化和聚集的tau無法清除,形成神經(jīng)纖維纏結(jié),而導(dǎo)致神經(jīng)退行性變。
[Abstract]:Part 1 regulation of O-OlcNAc glycosylation on Insulin-PI3K-AKT signaling pathway
Objective:
The effect of O-GlcNAc glycosylation on Insulin-PI3K-AKT signaling pathway was studied in different cells.
Method:
HEK-293FT, HepG2, N2a cells and primary cultured hippocampal neurons overexpress or downregulate O-GlcNAc glycosyltransferase OGT, or use inhibitors that regulate the key enzymes of O-GlcNAc glycosylation to treat cells and change the level of intracellular O-GlcNAc glycosylation. The method of immunoprecipitation can be used to study the Insulin-PI3K-AKT signaling pathway. The effects of O-GlcNAc glycosylation on the phosphorylation and activity of AKT and GSK-3 beta in different cells were analyzed by Western blot.
Result:
1) in HEK-293FT cells, the immunoblotting and immunoblotting analysis showed that AKT and GSK-3 beta were the O-GlcNAc glycosylated protein in the Insulin-PI3K-AKT signaling pathway.
2) under different culture conditions, the change of O-GlcNAc glycosylation level of HEK-293FT cells affects the negative regulation of.O-GlcNAc glycosylation of PI3K-AKT signaling pathway, Thr308 and Ser473 phosphorylation level, changes its activity, reduces the intracellular O-GlcNAc glycosylation and downregulates the phosphorylation of GSK-3 beta Ser9, but increases the O-GlcNAc glycosylation of the cell to GSK-3 beta. The phosphorylation of Ser9 has no effect
3) Changes of O-GlcNAc glycosylation level in HepG2 cells under different culture conditions had no significant effect on GSK-3 beta phosphorylation of AKT.
4) O-GlcNAc glycosylation regulates AKT phosphorylation in N2a cells and primary cultured mouse hippocampal neurons, but has no effect on GSK-3 beta phosphorylation.
Conclusion:
This study shows that the regulation of O-GlcNAc glycosylation on AKT and GSK-3 beta is protein specific and cell specific.Insulin-PI3K-AKT plays different roles in different organs, tissues and cells. The regulation of O-GlcNAc glycosylation also exists in different manifestations. In the neuron cell, O-GlcNAc glycosylation regulates the activity of AKT.
The second part is the effect of glycosylation of O-GlcNAc on apoptosis in cerebral ischemia.
Objective:
To study whether and how O-GlcNAc glycosylation induces apoptosis and to explore the effect of elevated O-GlcNAc glycosylation on apoptosis in the early stage of cerebral ischemia.
Method:
Protein immunoblotting and tissue immunofluorescence staining analysis of Middle Cerebral Artery Occlusion (MCAO) cerebral ischemia model in mice at different time O-GlcNAc glycosylation changes and AKT phosphorylation level.Caspase3 activity assay and Tunel determination of apoptosis in the hippocampus of mice in early cerebral ischemia. Cultured HEK-293FT cells, overexpressing OGT or shOGT down regulation of OGT expression to change the level of O-GlcNAc glycosylation, detection of cell viability by MTT, fluorescence staining to observe the morphology of nuclei, AnnexinV/PI flow cytometry to detect apoptotic cells, protein immunoblotting to analyze the activation of the early dying symbol Caspase3 and the hydrolysis of PAPR. The effects of glycosylation of O-GlcNAc on AKT were analyzed by immunoblotting and site-directed mutagenesis to explore whether O-GlcNAc glycosylation affects apoptosis by regulating AKT.
Result:
1) the results of protein immunoblotting and tissue immunofluorescence staining showed that the O-GlcNAc glycosylation of hippocampal tissue in the early cerebral ischemia of MCAO model in mice was increased, the activity of Caspase3 increased, and apoptotic cells were found in Tunel staining.
2) over expression of OGT in HEK293FT cells, cell viability decreased, nuclear concentration, fracture, and apoptotic like changes. Flow cytometry detected more apoptotic cells. Protein immunoblotting analysis showed that O-GlcNAc glycosylation, Caspase3 activation, and PARP egg white were hydrolyzed.
3) Thr308 and Ser473 of AKT are modified by O-GlcNAc glycosylation. Overexpression of OGT increases O-GlcNAc glycosylation, promotes the glycosylation of AKT, reduces the activity of AKT, causes the decrease of Bad phosphorylation in the downstream substrate, and then activates Caspase3 to induce apoptosis. It can not reverse the apoptosis induced by OGT.
4) There was a negative correlation between O-GlcNAc glycosylation and AKT phosphorylation in ischemic hippocampus.
Conclusion:
The Thr308 and Ser473 of AKT are modified by phosphorylation and glycosylation. In the early stage of cerebral ischemia, the O-GlcNAc glycosylation in the cells increased due to the stress response, and the phosphorylation and activity of AKT decreased, the BAD of phosphorylation was reduced, and the Caspase3 was activated through a series of reactions, and apoptosis occurred. Therefore, O-GlcNAc glycosylation was in the early stage of cerebral ischemia. Cell apoptosis may play an important role.
In the third part, O-GlcNAc glycosylation of F in the brain of patients with Alzheimer's disease affects FOXO1 mediated autophagy and Tau lesions.
Objective:
To investigate the function of O-GlcNAc glycosylation on the function of the transcription factor FoxO1, the effect of O-GlcNAc glycosylation on FoxO1 mediated tau lesions in Alzheimer's disease patients was investigated.
Method:
The expression of OGT or shOGT down regulated the expression of OGT in HEK-293FT cells. Protein immunoblotting was used to detect the effect of O-GlcNAc glycosylation on FoxO1. Protein synthesis and degradation inhibitors were used to treat cells. Protein immunoblotting and real-time quantitative PCR were used to study the pathway of O-GlcNAc glycosylation to regulate FoxO1 protein level. Immunoprecipitation technique was used. To study whether FoxO1 was modified by O-GlcNAc glycosylation and how to affect its own degradation. Protein immunoblotting was used to analyze FoxO1 in nuclei and cytoplasm, to investigate whether O-GlcNAc glycosylation changes affect the cell distribution of FoxO1, change the level of intracellular O-GlcNAc glycosylation, detect the luciferase activity of the FoxO1 reporter gene, and real-time quantitative PCR detection Fox O1 target gene expression, protein immunoblotting to detect the effect of FoxO1 on autophagy, and to investigate whether the O-GlcNAc glycosylation changes affect the activity of FoxO1. Using the neuron specific knockout of the OGT mice, the protein immunoblotting technique was used to detect the O-GlcNAc glycosylation changes, the protein and phosphorylation levels of AKT and foxO1, and the correlation between autophagy and proteasome. Protein level, One trail object recognition, Morris water maze, and Reversal Morris water maze test the learning and memory function of OGT KO mice. Protein immunoblotting and immunofluorescence staining were used to analyze the level of O-GlcNAc glycosylation and FoxO1 in AD patients, the level of autophagy related proteins, and the accumulation of Tau.
Result:
1) To change the glycosylation of O-GlcNAc in HEK-293FT cells not only affects the phosphorylation level of FoxO1 protein by regulating the activity of AKT, but also changes the protein level of FoxO1.
2) elevated O-GlcNAc glycosylation inhibits FoxO1 degradation through ubiquitin proteasome pathway.
3) FoxO1 itself can be modified by O-GlcNAc glycosylation, and when O-GlcNAc glycosylated modification increases, its own ubiquitination is reduced, and the degradation of ubiquitin proteasome pathway is inhibited.
4) O-GlcNAc glycosylation of FoxO1 increased its transcriptional activity and enhanced autophagy, but it did not affect its intracellular distribution.
5) The levels of O-GlcNAc glycosylation and FoxO1 in the forebrain neuron-specific OGT-knockout mice decreased, and their autophagy was down-regulated.
6) the level of O-GlcNAc glycosylation in the brain of AD patients, the level of FoxO1 protein, the increase of P62 protein level and the decrease of LC3 suggest the decrease of autophagy, and the protein level of FoxO1 is negatively correlated with the accumulation of Tau in the AD brain.
Conclusion:
The transcription factor FoxO1 is modified by O-GlcNAc glycosylation to enhance its stability. The reduced O-GlcNAc glycosylation level in the AD brain degrade and degrade the stability of FoxO1, and is regulated by its regulation of autophagic function, and the phosphorylation and aggregation of tau can not be removed, forming neurofibrillary tangles, resulting in neurodegenerative changes.
【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R749.16

【共引文獻(xiàn)】

相關(guān)期刊論文 前10條

1 李祥;楊華;;Bcl-2與缺血性腦血管疾病關(guān)系的研究進(jìn)展[J];國外醫(yī)學(xué)(老年醫(yī)學(xué)分冊);2001年02期

2 賈和平;單純皰疹病毒Ⅰ型載體神經(jīng)科應(yīng)用進(jìn)展[J];國外醫(yī)學(xué).神經(jīng)病學(xué)神經(jīng)外科學(xué)分冊;2001年04期

3 楊衛(wèi)民,周農(nóng);雌激素對缺血性腦損傷的保護(hù)作用及機(jī)制[J];國外醫(yī)學(xué).神經(jīng)病學(xué)神經(jīng)外科學(xué)分冊;2004年05期

4 賈和平,鄭榮珍;單純皰疹病毒Ⅰ型載體構(gòu)建在神經(jīng)系統(tǒng)疾病治療中的應(yīng)用[J];國外醫(yī)學(xué)(臨床生物化學(xué)與檢驗(yàn)學(xué)分冊);2002年04期

5 曹云燕;蔡圣朝;崔倩倩;張瑜;王金;費(fèi)愛華;朱才豐;;行氣調(diào)神針刺療法對缺血性腦卒中后抑郁模型大鼠腦左前皮質(zhì)及海馬cAMP含量、PKA和PKC活性的影響[J];甘肅中醫(yī)學(xué)院學(xué)報(bào);2013年04期

6 蒲蜀湘;吳培基;饒從磊;聶萬峰;陳盛強(qiáng);孫衛(wèi)文;;豐富環(huán)境對局灶性腦梗死大鼠曠場和水迷宮行為學(xué)及Nogo-A蛋白表達(dá)的影響[J];廣東醫(yī)學(xué);2013年16期

7 傅宏慶;盧煒;劉靜;賈紅;;大鼠局灶性腦缺血后適應(yīng)動物模型的建立與評估[J];中國畜牧獸醫(yī);2013年08期

8 何青;唐振剛;任玉奇;王陳維;王郡;陳怡;李正莉;;小膠質(zhì)細(xì)胞活化對癲癇發(fā)病的影響[J];中國組織化學(xué)與細(xì)胞化學(xué)雜志;2013年04期

9 呂凱;李鳳;龔標(biāo);李學(xué)智;黃思琴;伍芳;王力;;電針對軸突生長導(dǎo)向因子-1和臂板蛋白3a在局灶性腦梗死大鼠腦皮質(zhì)表達(dá)的影響[J];第三軍醫(yī)大學(xué)學(xué)報(bào);2013年18期

10 王凱華;黃龍堅(jiān);黃建民;;丹參酮ⅡA磺酸鈉對大鼠腦缺血再灌注后ERK信號通路的影響[J];廣西中醫(yī)藥;2013年04期

相關(guān)會議論文 前10條

1 向勤;胡微煦;蒲明;文珠;何丹;朱喜玲;胡國柱;;山藥多糖抗缺氧/復(fù)氧誘導(dǎo)的神經(jīng)細(xì)胞凋亡實(shí)驗(yàn)研究[A];第十一次中國中西醫(yī)結(jié)合實(shí)驗(yàn)醫(yī)學(xué)學(xué)術(shù)研討會論文匯編[C];2013年

2 胡微煦;向勤;文珠;何丹;夏曉健;胡國柱;;白術(shù)多糖抗神經(jīng)細(xì)胞缺氧性凋亡作用及機(jī)制[A];第十一次中國中西醫(yī)結(jié)合實(shí)驗(yàn)醫(yī)學(xué)學(xué)術(shù)研討會論文匯編[C];2013年

3 仲愛芹;徐士欣;張軍平;李偉;;丹酚酸B干預(yù)大鼠腦缺血再灌注損傷炎癥反應(yīng)的實(shí)驗(yàn)研究[A];第十一屆全國博士生學(xué)術(shù)年會（生物醫(yī)藥專題）論文集（下冊，墻報(bào)P25-P48）[C];2013年

4 徐偉;胡建鵬;王鍵;;益氣活血方和補(bǔ)腎生髓方對局灶性腦缺血再灌注大鼠Ctnnb1和Krt1基因及其蛋白表達(dá)的影響[A];第九次全國中西醫(yī)結(jié)合基礎(chǔ)理論研究學(xué)術(shù)研討會論文匯編[C];2013年

5 江愛娟;葉銘鋼;王浩;胡建鵬;;補(bǔ)腎生髓方和益氣活血方對腦缺血損傷大鼠Nogo-A、OMgp、MAG蛋白表達(dá)的影響[A];第九次全國中西醫(yī)結(jié)合基礎(chǔ)理論研究學(xué)術(shù)研討會論文匯編[C];2013年

6 譚輝;王鍵;胡建鵬;何玲;尹婷婷;菅威;;腦絡(luò)欣通對MCAO大鼠空間認(rèn)知功能和rCBF的影響[A];第九次全國中西醫(yī)結(jié)合基礎(chǔ)理論研究學(xué)術(shù)研討會論文匯編[C];2013年

7 Jun Liao;Xing Xia;Guo-zuo Wang;Yong-mei Shi;Jin-wen Ge;;NTE Treatment Results in Increased Fpn Expression in Hippocampus of Rats Subjected to Cerebral Ischemia[A];第九次全國中西醫(yī)結(jié)合基礎(chǔ)理論研究學(xué)術(shù)研討會論文匯編[C];2013年

8 黃愷飛;GD zhang;YQ Huang;刁勇;;Wogonin induces apoptosis and downregulates survivin in human breast cancer MCF-7 cells by modulating PI3K-AKT pathway[A];第十一屆全國博士生學(xué)術(shù)年會（生物醫(yī)藥專題）論文集（下冊，墻報(bào)P25-P48）[C];2013年

9 李芳君;;羥基紅花黃色素A對腦缺血大鼠腦組織細(xì)胞間黏附分子1表達(dá)的影響(已發(fā)表)[A];2013年廣東省藥師周大會論文集[C];2013年

10 Jianbin Zhang;Rui Cao;Tongjian Cai;Michael Aschner;Fang Zhao;Ting Yao;Yaoming Chen;Zipeng Cao;Wenjing Luo;Jingyuan Chen;;The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration[A];第十一屆全國博士生學(xué)術(shù)年會（生物醫(yī)藥專題）論文集（中冊，墻報(bào)P1-P24）[C];2013年

相關(guān)博士學(xué)位論文 前10條

1 孫寶柱;氟比洛芬酯對大鼠局灶性腦缺血再灌注損傷的保護(hù)作用及機(jī)制研究[D];山東大學(xué);2011年

2 李兵;胰島素對缺血性腦損傷中樞保護(hù)作用實(shí)驗(yàn)研究[D];第四軍醫(yī)大學(xué);2001年

3 李志欣;局灶性腦缺血溶栓聯(lián)合神經(jīng)保護(hù)的實(shí)驗(yàn)研究[D];天津醫(yī)科大學(xué);2002年

4 卞杰勇;雌激素對大鼠局灶性腦缺血保護(hù)作用的實(shí)驗(yàn)研究[D];蘇州大學(xué);2002年

5 朱炬;大鼠局灶性腦缺血再灌注后神經(jīng)元損傷與caspase-9及其相關(guān)因素的表達(dá)及調(diào)節(jié)的研究[D];天津醫(yī)科大學(xué);2003年

6 任小巧;老齡大鼠腦缺血/再灌注細(xì)胞凋亡及相關(guān)基因表達(dá)和腦脈通對其影響[D];北京中醫(yī)藥大學(xué);2003年

7 余曉慧;電針抗局灶性腦缺血大鼠的細(xì)胞凋亡和基因調(diào)控機(jī)制的實(shí)驗(yàn)研究[D];湖北中醫(yī)學(xué)院;2004年

8 曲友直;神經(jīng)保護(hù)劑聯(lián)合應(yīng)用對局灶性腦缺血再灌注損傷的保護(hù)作用及其機(jī)制研究[D];第四軍醫(yī)大學(xué);2004年

9 李昒源;“醒腦開竅”針法對局灶性腦缺血模型大鼠基底節(jié)蛋白質(zhì)組學(xué)影響的研究[D];天津中醫(yī)學(xué)院;2005年

10 袁盾;腦缺血預(yù)處理相關(guān)新基因Mipu1的表達(dá)，亞細(xì)胞定位及其小鼠同源基因的克隆[D];中南大學(xué);2006年

相關(guān)碩士學(xué)位論文 前10條

1 劉春寒;依達(dá)拉奉對慢性腦缺血鼠認(rèn)知功能障礙與TGF-β_1、Bc1-2、MDA、SOD陽性表達(dá)影響的研究[D];泰山醫(yī)學(xué)院;2007年

2 吳月鵬;白花丹參預(yù)處理對大鼠局灶性腦缺血Bcl-2和Bax的影響[D];泰山醫(yī)學(xué)院;2011年

3 左歡;白花丹參藥理性預(yù)適應(yīng)對缺血/缺氧神經(jīng)損傷的保護(hù)作用及機(jī)制研究[D];泰山醫(yī)學(xué)院;2011年

4 項(xiàng)永生;大鼠顱腦冷凍傷后腦水腫和神經(jīng)元凋亡的變化及其治療探討[D];暨南大學(xué);2001年

5 劉健;針刺對多發(fā)梗塞性癡呆模型大鼠腦細(xì)胞凋亡相關(guān)基礎(chǔ)bcl-2與bax的影響[D];天津中醫(yī)學(xué)院;2002年

6 陳紅兵;腦缺血再灌流損傷神經(jīng)細(xì)胞凋亡與Bcl-2和Caspase-3的關(guān)系[D];青島大學(xué);2002年

7 趙艷霞;光化學(xué)法MCAO鼠溶栓及腦保護(hù)治療的實(shí)驗(yàn)研究[D];鄭州大學(xué);2002年

8 王海濤;補(bǔ)陽還五湯對動粥大鼠腦缺血再灌注誘導(dǎo)的細(xì)胞凋亡的影響[D];山東中醫(yī)藥大學(xué);2003年

9 肖麗軍;bFGF在轉(zhuǎn)染bcl-2基因治療大鼠局灶性腦缺血表達(dá)的研究[D];中國醫(yī)科大學(xué);2004年

10 肖峰;氯胺酮對小鼠海馬缺血再灌注誘導(dǎo)相關(guān)基因表達(dá)影響[D];武漢大學(xué);2004年

，

本文編號：2167710