NSF ATP酶失活导致脑缺血再灌注后神经元损伤机制的研究
发布时间：2020-12-02 06:45
缺血性脑血管病具有高发病率、高致残性的特点,给患者遗留长期的神经功能缺损,与癌症及心血管疾病并称为威胁人类生存的三大疾病。其发病的主要原因是由于颅内血管重度狭窄或堵塞,以及心脏供血不足等导致局部或全脑组织血液供应下降而引发的神经功能缺损综合征。虽然临床上已采用颈内动脉内膜剥脱术、血管内支架置入术及颅内外血管搭桥术等方法用于恢复缺血区域的血液供应,但是仍然无法从根本上解决缺血后再灌注引发的脑损伤,是目前影响缺血性脑血管病疗效与预后最主要的原因。前几十年对于缺血性脑卒中的研究主要针对神经兴奋性毒性（neurotoxicity）、氧化应激反应、神经炎症以及血管及神经元单位（the neurovascular unit）等领域。但是,近期越来越多的研究发现,脑缺血后膜蛋白运输障碍对再灌注性神经元损伤起至关重要的作用。NSF ATPase,又名N-乙基马来酰亚胺敏感性因子（NSF）ATP酶,是参与膜融合最为关键的因子,实现将囊泡从一个细胞膜组件转移至另一个细胞膜组件。在这个过程中,两个连接膜上的SNARE蛋白形成一个紧密的复合物帮助实现囊泡与靶膜的融合。一旦发生膜融合,NSF ATPase就利用...
【文章来源】：吉林大学吉林省 211工程院校 985工程院校 教育部直属院校
【文章页数】：101 页
【学位级别】：博士
【部分图文】：
膜蛋白运输及NSF介导的囊泡融合
7图1.2 共聚焦显微镜下观察标记NSF抗体的CA1区神经元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 脑缺血后高尔基体、运输囊泡以及晚期内涵体聚集的超微结构表征：高尔基体、早期内涵体和晚期内涵体作为最具活力的细胞器结构，其膜表面的SNAREs浓度含量最高，可有效地结合SNAP衔接蛋白和NSF，因此需要最高数量的NSF来解离SNAREs复合物用于重新产生有活性的SNAREs[32]。Dalal S.等人通过对表达NSFE329Q突变体的转基因小鼠的研究发现，分散在高尔基膜表面的NSF似乎并不与内质网结合，而是在细胞周围移动并在细胞核周围聚集，这些高尔基体小泡与ER之间缺乏融合最可能的解释是内质网膜表面SNAREs其结合SNAP衔接蛋白和NSF能力相比于高尔基体和内涵体膜表面的SNAREs低，导致内质网膜表面产生的SNAREs复合物含量随之降低，因此需要相对低水平的NSF来分解SNAREs复合物[33]。由此证明
图1.3 EM下观察缺血后高尔基体、运输囊泡以及晚期内涵体的超微结构表征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 大量释放导致脑缺血再灌注后神经元损伤
本文编号：2895129
【文章来源】：吉林大学吉林省 211工程院校 985工程院校 教育部直属院校
【文章页数】：101 页
【学位级别】：博士
【部分图文】：
膜蛋白运输及NSF介导的囊泡融合
7图1.2 共聚焦显微镜下观察标记NSF抗体的CA1区神经元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 脑缺血后高尔基体、运输囊泡以及晚期内涵体聚集的超微结构表征：高尔基体、早期内涵体和晚期内涵体作为最具活力的细胞器结构，其膜表面的SNAREs浓度含量最高，可有效地结合SNAP衔接蛋白和NSF，因此需要最高数量的NSF来解离SNAREs复合物用于重新产生有活性的SNAREs[32]。Dalal S.等人通过对表达NSFE329Q突变体的转基因小鼠的研究发现，分散在高尔基膜表面的NSF似乎并不与内质网结合，而是在细胞周围移动并在细胞核周围聚集，这些高尔基体小泡与ER之间缺乏融合最可能的解释是内质网膜表面SNAREs其结合SNAP衔接蛋白和NSF能力相比于高尔基体和内涵体膜表面的SNAREs低，导致内质网膜表面产生的SNAREs复合物含量随之降低，因此需要相对低水平的NSF来分解SNAREs复合物[33]。由此证明
图1.3 EM下观察缺血后高尔基体、运输囊泡以及晚期内涵体的超微结构表征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 大量释放导致脑缺血再灌注后神经元损伤
本文编号：2895129
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