RNA editing of AMPA receptor subunit GluR2 in ischemia
缺血中 AMPA 受体亚基 GluR2 的 RNA 编辑
基本信息
- 批准号:7760657
- 负责人:
- 金额:$ 30.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-05-15 至 2012-01-31
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAddressAdenosineAreaCause of DeathCyclic AMP-Responsive DNA-Binding ProteinCytoplasmic GranulesDRADA2b proteinDataDefectDeveloped CountriesDiseaseEnzymesEpileptogenesisGene ExpressionGene SilencingGenerationsGenesGluR2 subunit AMPA receptorGlutamate ReceptorGlutamatesHippocampus (Brain)IndividualIschemiaIschemic Neuronal InjuryIschemic StrokeLeadN-Methyl-D-Aspartate ReceptorsNerve DegenerationNeuronal InjuryNeuronsNuclearPatternPermeabilityPhysiologicalPredispositionPropertyProsencephalonRNARNA EditingRattusReportingResearch PersonnelResistanceSeizuresSiteSmall Interfering RNASynapsesWorkdentate gyrusdesensitizationdsRNA adenosine deaminasehippocampal pyramidal neuronneuron lossneuronal survivalresearch studyrestorationtranscription factorvector
项目摘要
Ischemic stroke is the third leading cause of death in developed countries. A critical feature of the disease is
a highly selective pattern of neuronal loss; certain identifiable subsets of neurons, particularly CA1
pyramidal neurons in the hippocampus, are severely damaged while others remain intact. A step in this
selective neuronal injury involves Ca2+ entry through Ca2+-permeable AMPA receptor channels. AMPA
receptors are a major subtype of glutamate receptors (GluRs) that are assembled from GluR1-4 subunits.
Ca2+ permeability of the channels is dominated by GluR2 RNA editing at the Q/R site; edited GluR2(R)
subunits form Ca2+-impermeable channels, whereas unedited GluR2(Q) channels allow Ca2+ entry. In
most CA1 neurons, AMPA receptor channels contain GluR2(R), and thus are impermeable to Ca2+ flow.
Recently, we have identified that transient forebrain ischemia selectively disrupts GluR2 Q/R site editing and
hence induces injurious Ca2+ entry through AMPA receptor channels into vulnerable CA1 neurons. We
have also shown that impaired GluR2 Q/R site editing is closely correlated with reduced expression of
ADAR2 (short for adenosine deaminase acting on RNA) gene, a nuclear enzyme responsible for GluR2 Q/R
site editing. We thus hypothesize that reduced expression of ADAR2 gene is responsible for the impaired
GluR2 Q/R site editing. To address this hypothesis directly, we will determine if restoration of ADAR2 gene
expression rescues GluR2 Q/R site editing and in turn blocks Ca2+ permeability of AMPA receptor
channels, leading to the survival of vulnerable neurons in the post-ischemic rats. Overall, this project will
have two specific aims:
Specific Aim 1: To determine whether restoration of ADAR2 gene expression blocks Ca2+ entry through
AMPA receptor channels and rescues vulnerable neurons in the post-ischemic rats.
Specific Aim 2: To determine if generation of stable ADAR2 gene silencing induces degeneration of
ischemia-insensitive neurons, and if degeneration of ADAR2-deficient neurons results from RNA editing
deficits of one or more glutamate receptor subunits.
Together, this project will identify that ADAR2-dependent GluR2 Q/R site editing determines vulnerability of
neurons to ischemia. Thus, this work will define a promising target for stoke therapy.
缺血性中风是发达国家第三大死亡原因。该疾病的一个重要特征是
神经元丢失的高度选择性模式;某些可识别的神经元子集,特别是 CA1
海马体中的锥体神经元严重受损,而其他神经元则完好无损。这一步
选择性神经元损伤涉及 Ca2+ 通过 Ca2+ 可渗透的 AMPA 受体通道进入。 AMPA
受体是谷氨酸受体 (GluR) 的主要亚型,由 GluR1-4 亚基组装而成。
通道的 Ca2+ 通透性由 Q/R 位点的 GluR2 RNA 编辑控制;编辑后的 GluR2(R)
亚基形成 Ca2+ 不可渗透的通道,而未经编辑的 GluR2(Q) 通道允许 Ca2+ 进入。在
大多数 CA1 神经元、AMPA 受体通道含有 GluR2(R),因此对 Ca2+ 流是不可渗透的。
最近,我们发现短暂的前脑缺血选择性地破坏 GluR2 Q/R 位点编辑和
因此,诱导有害的 Ca2+ 通过 AMPA 受体通道进入脆弱的 CA1 神经元。我们
还表明受损的 GluR2 Q/R 位点编辑与减少的表达密切相关
ADAR2(作用于 RNA 的腺苷脱氨酶的缩写)基因,一种负责 GluR2 Q/R 的核酶
网站编辑。因此,我们推测 ADAR2 基因表达的减少是造成损伤的原因。
GluR2 Q/R 位点编辑。为了直接解决这个假设,我们将确定 ADAR2 基因的恢复是否
表达挽救了 GluR2 Q/R 位点编辑,进而阻断 AMPA 受体的 Ca2+ 通透性
通道,导致缺血后大鼠中脆弱神经元的存活。总体而言,该项目将
有两个具体目标:
具体目标 1:确定 ADAR2 基因表达的恢复是否通过以下方式阻止 Ca2+ 进入:
AMPA 受体通道并拯救缺血后大鼠的脆弱神经元。
具体目标 2:确定稳定 ADAR2 基因沉默的产生是否会导致 ADAR2 基因退化
缺血不敏感神经元,以及 ADAR2 缺陷型神经元的退化是由 RNA 编辑引起的
一种或多种谷氨酸受体亚基的缺陷。
总之,该项目将确定 ADAR2 依赖性 GluR2 Q/R 位点编辑决定了
神经元缺血。因此,这项工作将为中风治疗确定一个有希望的目标。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation.
- DOI:10.1016/j.neuron.2012.02.003
- 发表时间:2012-02-23
- 期刊:
- 影响因子:16.2
- 作者:Yang Y;Shu X;Liu D;Shang Y;Wu Y;Pei L;Xu X;Tian Q;Zhang J;Qian K;Wang YX;Petralia RS;Tu W;Zhu LQ;Wang JZ;Lu Y
- 通讯作者:Lu Y
DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke.
- DOI:10.1016/j.cell.2009.12.055
- 发表时间:2010-01-22
- 期刊:
- 影响因子:64.5
- 作者:Tu W;Xu X;Peng L;Zhong X;Zhang W;Soundarapandian MM;Balel C;Wang M;Jia N;Zhang W;Lew F;Chan SL;Chen Y;Lu Y
- 通讯作者:Lu Y
Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity.
- DOI:10.1016/j.neuron.2008.10.015
- 发表时间:2008-12-10
- 期刊:
- 影响因子:16.2
- 作者:Kim D;Frank CL;Dobbin MM;Tsunemoto RK;Tu W;Peng PL;Guan JS;Lee BH;Moy LY;Giusti P;Broodie N;Mazitschek R;Delalle I;Haggarty SJ;Neve RL;Lu Y;Tsai LH
- 通讯作者:Tsai LH
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{{ truncateString('YOUMING LU', 18)}}的其他基金
DAPK1 regulation of NMDA receptors in ischemic neuronal death
DAPK1 对 NMDA 受体在缺血性神经元死亡中的调节
- 批准号:
7675965 - 财政年份:2008
- 资助金额:
$ 30.71万 - 项目类别:
DAPK1 regulation of NMDA receptors in ischemic neuronal death
DAPK1 对 NMDA 受体在缺血性神经元死亡中的调节
- 批准号:
7888146 - 财政年份:2008
- 资助金额:
$ 30.71万 - 项目类别:
DAPK1 regulation of NMDA receptors in ischemic neuronal death
DAPK1 对 NMDA 受体在缺血性神经元死亡中的调节
- 批准号:
7522367 - 财政年份:2008
- 资助金额:
$ 30.71万 - 项目类别:
DAPK1 regulation of NMDA receptors in ischemic neuronal death
DAPK1 对 NMDA 受体在缺血性神经元死亡中的调节
- 批准号:
8142986 - 财政年份:2008
- 资助金额:
$ 30.71万 - 项目类别:
DAPK1 regulation of NMDA receptors in ischemic neuronal death
DAPK1 对 NMDA 受体在缺血性神经元死亡中的调节
- 批准号:
7786536 - 财政年份:2008
- 资助金额:
$ 30.71万 - 项目类别:
DAPK1 regulation of NMDA receptors in ischemic neuronal death
DAPK1 对 NMDA 受体在缺血性神经元死亡中的调节
- 批准号:
8117740 - 财政年份:2008
- 资助金额:
$ 30.71万 - 项目类别:
RNA editing of AMPA receptor subunit GluR2 in ischemia
缺血中 AMPA 受体亚基 GluR2 的 RNA 编辑
- 批准号:
7766886 - 财政年份:2006
- 资助金额:
$ 30.71万 - 项目类别:
RNA editing of AMPA receptor subunit GluR2 in ischemia
缺血中 AMPA 受体亚基 GluR2 的 RNA 编辑
- 批准号:
7140760 - 财政年份:2006
- 资助金额:
$ 30.71万 - 项目类别:
RNA editing of AMPA receptor subunit GluR2 in ischemia
缺血中 AMPA 受体亚基 GluR2 的 RNA 编辑
- 批准号:
7233658 - 财政年份:2006
- 资助金额:
$ 30.71万 - 项目类别:
RNA editing of AMPA receptor subunit GluR2 in ischemia
缺血中 AMPA 受体亚基 GluR2 的 RNA 编辑
- 批准号:
7354764 - 财政年份:2006
- 资助金额:
$ 30.71万 - 项目类别:
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