MECHANISMS OF INCREASED EXCITATORY AMINOACID IN ISCHEMIA
MECHANISMS OF INCREASED EXCITATORY AMINOACID IN ISCHEMIA
批准号:
2892071
负责人:
Harold K Kimelberg
金额:
$20.2万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1996
资助国家:
美国
项目状态:
已结题
起止时间:
1996-05-01 至 2001-03-31
关键词:
aspartate astrocytes calcium cerebral ischemia /hypoxia excitatory aminoacid glial fibrillary acidic protein glutamate receptor glutamate transporter glutamates high performance liquid chromatography hippocampus immunocytochemistry kainate laboratory rat microdialysis neurons neuropharmacology neurotoxins potassium rubidium sodium synaptosomes temperature tissue /cell culture
中文摘要
中枢神经系统损伤的一个主要假说是细胞外增加
在这种损伤后发生的兴奋性氨基酸(EAA)水平
神经细胞内钙离子水平升高是由于细胞过度激活
谷氨酸受体,导致神经元损伤和死亡。这项计划是
有几条证据支持,例如,用
谷氨酸受体阻滞剂或抑制大鼠体内升高的EAA水平
活体是有保护作用的。与大量的工作形成鲜明对比
EAA水平升高的影响,细胞来源和
耳朵增加的机制还很少被研究。两者都增加了
释放和减少摄取将有助于增加EaAs。
令人惊讶的是,在最近的微透析研究中,大部分增加的EAA
在动物缺血模型中发现的水平是钙
不敏感,表明神经末梢的胞吐释放
并不是导致地产代理监管局水平上升的主要原因,而另一个
必须考虑机制和来源。
细胞外钾在缺血时显著升高,且两种钙非依赖性
EaAs的体外释放机制已被确定,它们是
受K升高的刺激。这些都是谷氨酸转运体的逆转
在突触体、培养的神经元和星形胶质细胞中可见,肿胀-
诱导星形胶质细胞释放EaAs。我们将学习小学
星形胶质细胞培养和突触体来源于海马区和
培养的小脑颗粒细胞用于我们的体外研究,因为有
没有海马神经元培养能提供足够数量的
用于运输研究的细胞。通过确认中看到的运输商表格
不同的体外制剂我们会看看它们是否有不同的
反转特征。导致地产代理监管局增加的另一个主要因素
水平会抑制摄取,星形胶质细胞具有非常活跃的
星形胶质细胞特异性的EAA摄取系统。我们将研究抑制EAA
体外培养星形胶质细胞对中钾的摄取。使用数据
在体外获得不同的系统,我们将确定它们的
微透析对体内EaAs水平升高的贡献
大鼠海马区可逆性全脑缺血实验。在……里面
此外,我们将用胶质毒素产生局部的星形胶质细胞耗竭。
和神经元,并确定这些因素的影响
脑缺血诱导的EaS释放的程序。了解
EAA释放或摄取受损的不同来源和机制
它们在脑缺血和脑缺血时EAA水平升高中的作用
其他病理状态对解释当前的治疗方法至关重要
并设计出新的州。
英文摘要
A major hypothesis of CNS injury is that the increased extracellular
excitatory amino acid (EAA) levels which occur after such injuries cause
increased intra-neuronal calcium levels due to excessive activation of
glutamate receptors, leading to neuronal damage and death. This scheme is
supported by several lines of evidence such as, that treatment with
glutamate receptor blockers or inhibition of the increased EAA levels in
vivo are protective. In sharp contrast to the considerable body of work on
the effects of the increased EAA levels, the cellular sources and
mechanisms of the increased EAR have been little-studied. Both increased
release and decreased uptake would contribute to increased EAAs.
Surprisingly, in recent microdialysis studies, much of the increased EAA
levels seen in animal models of ischemia has been found to be Ca2+
insensitive, suggesting that exocytotic release from nerve terminals is
not a major contributor to the increased EAA levels, and that other
mechanisms and sources must be considered.
Extracellular K+ increases markedly in ischemia, and two Ca2+-independent
release mechanisms for EAAs have been identified in in vitro which are
stimulated by raised K+. These are reversal of the glutamate transporter
seen in synaptosomes and cultured neurons and astrocytes, and swelling-
induced release of EAAs seen in astrocytes. We will study primary
astrocyte cultures and synaptosomes derived from the hippocampus and
cultured cerebellar granule cells for our in vitro studies, as there are
no hippocampal neuronal cultures that provide sufficient quantities of
cells for transport studies. By confirming the transporter forms seen in
the different in vitro preparations we will see if they have different
reversal characteristics. Another major contributor to the increased EAA
levels would be inhibition of uptake and astrocytes have very active and
astrocyte-specific EAA uptake systems. We will study inhibition of EAA
uptake by increased medium K+ in astrocytes in vitro. Using the data
obtained on the different systems in vitro, we will determine their
contributions to the increased levels of EAAs in vivo by microdialysis
experiments in the rat hippocampus with reversible global ischemia. In
addition we will produce localized depletion of astrocytes with gliotoxins
and neurons by kainic acid, and determine the influence of these
procedures on the ischemia-induced release of EAAs. Understanding the
different sources and mechanisms of EAA release or impaired uptake and
their respective contributions to the elevated EAA levels in ischemia and
other pathological states is vital to interpretation of current therapies
for such states and devising new ones.
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Excitatory Amino Acid Release in Ischemia
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批准号:6330998
-
项目类别:
-
资助金额:$39.0万
-
财政年份:1996
-
负责人:Harold K Kimelberg
-
依托单位:
MECHANISMS OF INCREASED EXCITATORY AMINOACID IN ISCHEMIA
-
批准号:6187299
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项目类别:
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资助金额:$21.01万
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Excitatory Amino Acid Release in Ischemia
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批准号:6604067
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批准号:6898184
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Excitatory Amino Acid Release in Ischemia
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批准号:6655358
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Excitatory Amino Acid Release in Ischemia
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NEURAL INJURY AND BLOOD FLOW ALTERATION AFTER CNS TRAUMA
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依托单位:
NEURAL INJURY AND BLOOD FLOW ALTERATION AFTER CNS TRAUMA
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批准号:2268341
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项目类别:
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资助金额:$0.96万
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负责人:Harold K Kimelberg
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依托单位:
NEURAL INJURY AND BLOOD FLOW ALTERATION AFTER CNS TRAUMA
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项目类别:
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NEURAL INJURY AND BLOOD FLOW ALTERATION AFTER CNS TRAUMA
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SMALL INSTRUMENTATION GRANT
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批准号:3525615
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批准号:3407597
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项目类别:
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负责人:Harold K Kimelberg
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依托单位:
VOLUME REGULATION & MEMBRANE TRANSPORT IN ASTROCYTES
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批准号:2264927
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项目类别:
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资助金额:$17.23万
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财政年份:1986
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依托单位:
ION TRANSPORT AND VOLUME REGULATION IN ASTROCYTES
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批准号:3407604
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项目类别:
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资助金额:$7.73万
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依托单位:
国内基金
海外基金
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批准号:31760279
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项目类别:地区科学基金项目
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资助金额:35.0万元
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批准年份:2017
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负责人:丁银秀
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依托单位: