NSF ATP酶失活導(dǎo)致腦缺血再灌注后神經(jīng)元損傷機制的研究
發(fā)布時間：2020-12-02 06:45
缺血性腦血管病具有高發(fā)病率、高致殘性的特點,給患者遺留長期的神經(jīng)功能缺損,與癌癥及心血管疾病并稱為威脅人類生存的三大疾病。其發(fā)病的主要原因是由于顱內(nèi)血管重度狹窄或堵塞,以及心臟供血不足等導(dǎo)致局部或全腦組織血液供應(yīng)下降而引發(fā)的神經(jīng)功能缺損綜合征。雖然臨床上已采用頸內(nèi)動脈內(nèi)膜剝脫術(shù)、血管內(nèi)支架置入術(shù)及顱內(nèi)外血管搭橋術(shù)等方法用于恢復(fù)缺血區(qū)域的血液供應(yīng),但是仍然無法從根本上解決缺血后再灌注引發(fā)的腦損傷,是目前影響缺血性腦血管病療效與預(yù)后最主要的原因。前幾十年對于缺血性腦卒中的研究主要針對神經(jīng)興奮性毒性（neurotoxicity）、氧化應(yīng)激反應(yīng)、神經(jīng)炎癥以及血管及神經(jīng)元單位（the neurovascular unit）等領(lǐng)域。但是,近期越來越多的研究發(fā)現(xiàn),腦缺血后膜蛋白運輸障礙對再灌注性神經(jīng)元損傷起至關(guān)重要的作用。NSF ATPase,又名N-乙基馬來酰亞胺敏感性因子（NSF）ATP酶,是參與膜融合最為關(guān)鍵的因子,實現(xiàn)將囊泡從一個細胞膜組件轉(zhuǎn)移至另一個細胞膜組件。在這個過程中,兩個連接膜上的SNARE蛋白形成一個緊密的復(fù)合物幫助實現(xiàn)囊泡與靶膜的融合。一旦發(fā)生膜融合,NSF ATPase就利用...
【文章來源】：吉林大學(xué)吉林省 211工程院校 985工程院校 教育部直屬院校
【文章頁數(shù)】：101 頁
【學(xué)位級別】：博士
【部分圖文】：
膜蛋白運輸及NSF介導(dǎo)的囊泡融合
7圖1.2 共聚焦顯微鏡下觀察標記NSF抗體的CA1區(qū)神經(jīng)元Fig 1.2 Confocal microscopic images of CA1 neurons labeled with NSF antibody.Brainsections were obtained from a sham-operated control rat and rat subjected to 15 min of ischemiafollowed by 24 h of reperfusion. NSF is located in the peri-nuclear and dendritic truck (Sham,arrowheads), as well as in the neuropil (Sham, arrows) of sham-operated control CA1 neurons.NSF is mostly depleted from the CA1 neuronal perinuclear region and dendritic trunk (24h,arrowheads), but remains relatively at the sham control level in the CA1 neuropil (24h, arrows)at 24 h of reperfusion after transient cerebral ischemia.1.2.1.4 腦缺血后高爾基體、運輸囊泡以及晚期內(nèi)涵體聚集的超微結(jié)構(gòu)表征：高爾基體、早期內(nèi)涵體和晚期內(nèi)涵體作為最具活力的細胞器結(jié)構(gòu)，其膜表面的SNAREs濃度含量最高，可有效地結(jié)合SNAP銜接蛋白和NSF，因此需要最高數(shù)量的NSF來解離SNAREs復(fù)合物用于重新產(chǎn)生有活性的SNAREs[32]。Dalal S.等人通過對表達NSFE329Q突變體的轉(zhuǎn)基因小鼠的研究發(fā)現(xiàn)，分散在高爾基膜表面的NSF似乎并不與內(nèi)質(zhì)網(wǎng)結(jié)合，而是在細胞周圍移動并在細胞核周圍聚集，這些高爾基體小泡與ER之間缺乏融合最可能的解釋是內(nèi)質(zhì)網(wǎng)膜表面SNAREs其結(jié)合SNAP銜接蛋白和NSF能力相比于高爾基體和內(nèi)涵體膜表面的SNAREs低，導(dǎo)致內(nèi)質(zhì)網(wǎng)膜表面產(chǎn)生的SNAREs復(fù)合物含量隨之降低，因此需要相對低水平的NSF來分解SNAREs復(fù)合物[33]。由此證明
圖1.3 EM下觀察缺血后高爾基體、運輸囊泡以及晚期內(nèi)涵體的超微結(jié)構(gòu)表征Fig1.3 EM micrographs of hippocampal CA1 neurons stained with uranium-lead.CA1 tissue sections were obtained from rats subjected to non-ischemic sham surgery or 20min of ischemia followed by 24 h of reperfusion. a: Sham neuron shows normal roughendoplasmic reticulum (ER), ribosomal rosettes (small arrows), mitochondria (M), Golgiapparatus (G), late endosome (large arrow), and endolysosome (EL, as secondary lysosome)b:24 h reperfusedneuron shows accumulation of Golgi fragments (Gf), transport vesicles(arrowheads), enlarged late endosome (large arrows), monoribosomes (small arrows), andribosomal aggregates (stars). c and d: Higher magnifications of the insets of “a and b” showthat ELs and LE (arrow) from sham control neuron have intact lipid membranes, whereas anenlarged LE from the postischemic neuron has a number of membrane break damage(arrowheads). Scale bar = 0.5 μm.1.2.2 Cathepsin B 大量釋放導(dǎo)致腦缺血再灌注后神經(jīng)元損傷
本文編號：2895129
【文章來源】：吉林大學(xué)吉林省 211工程院校 985工程院校 教育部直屬院校
【文章頁數(shù)】：101 頁
【學(xué)位級別】：博士
【部分圖文】：
膜蛋白運輸及NSF介導(dǎo)的囊泡融合
7圖1.2 共聚焦顯微鏡下觀察標記NSF抗體的CA1區(qū)神經(jīng)元Fig 1.2 Confocal microscopic images of CA1 neurons labeled with NSF antibody.Brainsections were obtained from a sham-operated control rat and rat subjected to 15 min of ischemiafollowed by 24 h of reperfusion. NSF is located in the peri-nuclear and dendritic truck (Sham,arrowheads), as well as in the neuropil (Sham, arrows) of sham-operated control CA1 neurons.NSF is mostly depleted from the CA1 neuronal perinuclear region and dendritic trunk (24h,arrowheads), but remains relatively at the sham control level in the CA1 neuropil (24h, arrows)at 24 h of reperfusion after transient cerebral ischemia.1.2.1.4 腦缺血后高爾基體、運輸囊泡以及晚期內(nèi)涵體聚集的超微結(jié)構(gòu)表征：高爾基體、早期內(nèi)涵體和晚期內(nèi)涵體作為最具活力的細胞器結(jié)構(gòu)，其膜表面的SNAREs濃度含量最高，可有效地結(jié)合SNAP銜接蛋白和NSF，因此需要最高數(shù)量的NSF來解離SNAREs復(fù)合物用于重新產(chǎn)生有活性的SNAREs[32]。Dalal S.等人通過對表達NSFE329Q突變體的轉(zhuǎn)基因小鼠的研究發(fā)現(xiàn)，分散在高爾基膜表面的NSF似乎并不與內(nèi)質(zhì)網(wǎng)結(jié)合，而是在細胞周圍移動并在細胞核周圍聚集，這些高爾基體小泡與ER之間缺乏融合最可能的解釋是內(nèi)質(zhì)網(wǎng)膜表面SNAREs其結(jié)合SNAP銜接蛋白和NSF能力相比于高爾基體和內(nèi)涵體膜表面的SNAREs低，導(dǎo)致內(nèi)質(zhì)網(wǎng)膜表面產(chǎn)生的SNAREs復(fù)合物含量隨之降低，因此需要相對低水平的NSF來分解SNAREs復(fù)合物[33]。由此證明
圖1.3 EM下觀察缺血后高爾基體、運輸囊泡以及晚期內(nèi)涵體的超微結(jié)構(gòu)表征Fig1.3 EM micrographs of hippocampal CA1 neurons stained with uranium-lead.CA1 tissue sections were obtained from rats subjected to non-ischemic sham surgery or 20min of ischemia followed by 24 h of reperfusion. a: Sham neuron shows normal roughendoplasmic reticulum (ER), ribosomal rosettes (small arrows), mitochondria (M), Golgiapparatus (G), late endosome (large arrow), and endolysosome (EL, as secondary lysosome)b:24 h reperfusedneuron shows accumulation of Golgi fragments (Gf), transport vesicles(arrowheads), enlarged late endosome (large arrows), monoribosomes (small arrows), andribosomal aggregates (stars). c and d: Higher magnifications of the insets of “a and b” showthat ELs and LE (arrow) from sham control neuron have intact lipid membranes, whereas anenlarged LE from the postischemic neuron has a number of membrane break damage(arrowheads). Scale bar = 0.5 μm.1.2.2 Cathepsin B 大量釋放導(dǎo)致腦缺血再灌注后神經(jīng)元損傷
本文編號：2895129
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