SIGMA RECEPTOR SIGNALING IN FOCAL CEREBRAL ISCHEMIA
SIGMA RECEPTOR SIGNALING IN FOCAL CEREBRAL ISCHEMIA
批准号:
6565199
负责人:
JEFFREY R KIRSCH
金额:
$25.59万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-12-01 至 2002-11-30
关键词:
G protein autoradiography biological signal transduction brain disorder chemotherapy brain metabolism cerebral ischemia /hypoxia dopamine drug receptors excitatory aminoacid immunocytochemistry laboratory mouse laboratory rat ligands microdialysis neurochemistry neuroprotectants nitric oxide synthase nonhuman therapy evaluation piperidine reperfusion
中文摘要
兴奋性氨基酸是缺血性脑损伤的重要组成部分
机械装置。因为Sigma受体配体调节神经元的反应
药物对N-甲基-D-天冬氨酸受体的体外刺激作用
通过特定的Sigma配体识别位点,它们具有潜力
在中风中的治疗价值,可能与之无关
限制其临床应用的不良副作用
NMDA受体拮抗剂
4-苯基-1-(4-苯基丁基)哌啶(PPBP)是一种典型的异构体。
提供神经保护的受体配体,但其确切机制是
以前还没有在体内诱导出保护作用。中得出的结论
体外实验表明,Sigma受体配体可能会干扰
通过与兴奋性氨基酸相互作用引起的神经毒性
NMDA受体复合体。此外,Sigma受体配体可以有利地
减少兴奋性神经递质和儿茶酚胺的释放
缺血,特别是谷氨酸和多巴胺。这个项目的总体目标是
项目是定义体内信号传递过程,这一过程解释了
Sigma受体配体在短暂性脑缺血发作中的显著神经保护作用
局灶性缺血。一般的假设是,这些配体保护
通过独特的Sigma受体途径抑制兴奋性毒素
释放和NMDA激活,从而阻止随后的神经元
一氧化氮合酶(NNOS)激活与细胞死亡。具体目标
威尔:定义最有效的治疗范式--西格玛受体
配体PPBP在短暂性局灶性脑缺血中的作用;确定Sigma受体
激活抑制局灶性脑缺血损伤的兴奋性毒性机制;
表征基础和缺血后Sigma受体信号转导机制
在体内;确定Sigma受体是否介导了
神经保护是一氧化氮合酶构成的神经元亚型所特有的。
该方法将包括使用血管内线闭塞
大鼠和小鼠短暂性局灶性脑缺血模型,
微透析法测定自发和NMDA刺激的一氧化氮合酶活性,
ITS微透析法测定兴奋性氨基酸和多巴胺
代谢物,免疫化学检测G蛋白和
Sigma受体分布的放射自显影测量。这些
各种技术结合起来检验了Sigma受体配体
通过以下方式改善神经学结果(组织学和神经功能)
缺血和缺氧时对兴奋性氨基酸机制的干扰
通过G蛋白第二信使再灌流,所有这些最终
导致NO生成减少,脑损伤减轻。
英文摘要
Excitatory amino acids are an integral part of ischemic brain injury
mechanisms. Because sigma-receptor ligands modulate neuronal responses to
pharmacologic N-methyl D-aspartate (NMDA) receptor stimulation in vitro
via a specific sigma ligand recognition site, they are of potential
therapeutic value in stroke and may not be associate with the same
spectrum of undesired side-effects which limit the clinical utility of
NMDA receptor antagonists
4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is a prototypic sigma-
receptor ligand which provides neuroprotection but the exact mechanism of
protection has not been previously elicited in vivo. Conclusions from in
vitro experiments have suggested that sigma-receptor ligands may interfere
with excitatory amino acid-induced neurotoxicity by interacting with the
NMDA receptor complex. Further, sigma-receptor ligands may advantageously
decrease excitotoxic neurotransmitter and catecholamine release during
ischemia, specifically glutamate and dopamine. The overall goal of this
project is to define the in vivo signaling process that accounts for the
marked neuroprotective properties of sigma-receptor ligands in transient
focal ischemia. The general hypothesis is that these ligands protect the
brain by a unique sigma-receptor pathway which inhibits excitotoxin
release and NMDA activation, and, therefore, prevents consequent neuronal
nitric oxide synthase (nNOS) activation and cell death. The specific aims
will: define the most efficacious treatment paradigm sigma-receptor
ligand, PPBP, in transient focal ischemia; determine if sigma-receptor
activation inhibits excitotoxic mechanisms of focal ischemic brain injury;
characterize basal and post-ischemic sigma-receptor signaling mechanisms
in vivo; determine if sigma receptor mediated mechanisms of
neuroprotection are specific to the constitutive neuronal isoform of NOS.
The methodology will include use of an intravascular thread occlusion
model of transient focal ischemia in rodents (both rats and mice),
microdialysis measurement of spontaneous and NMDA-stimulated NOS activity,
microdialysis measurement of excitatory amino acids and dopamine with its
metabolites, immunochemistry for detection of G-protein and
autoradiography for measurement of sigma-receptor distribution. These
techniques are combined to test the hypothesis that sigma-receptor ligands
improve neurologic outcome (histology and neurologic function) by
interfering with excitatory amino acid mechanisms during ischemia and
reperfusion through a G-protein second messenger, all which ultimately
result in decreased production of NO and decreased brain injury.
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会议论文
Integrated and Translational Training in Anesthesiology Research
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批准号:7908786
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项目类别:
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资助金额:$12.16万
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财政年份:2008
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负责人:JEFFREY R KIRSCH
-
依托单位:
Integrated and Translational Training in Anesthesiology Research
-
批准号:8128688
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项目类别:
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资助金额:$11.93万
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财政年份:2008
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负责人:JEFFREY R KIRSCH
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依托单位:
Integrated and Translational Training in Anesthesiology Research
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批准号:8304232
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项目类别:
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资助金额:$0.0万
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财政年份:2008
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负责人:JEFFREY R KIRSCH
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依托单位:
Sigma Receptor Signaling in Focal Ischemia
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批准号:6825310
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项目类别:
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资助金额:$24.73万
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财政年份:2003
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负责人:JEFFREY R KIRSCH
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SIGMA RECEPTOR SIGNALING IN FOCAL CEREBRAL ISCHEMIA
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批准号:6410628
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资助金额:$25.59万
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SIGMA RECEPTOR SIGNALING IN FOCAL CEREBRAL ISCHEMIA
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批准号:6302750
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资助金额:$15.49万
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财政年份:1999
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SIGMA RECEPTOR SIGNALING IN FOCAL CEREBRAL ISCHEMIA
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批准号:6273690
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资助金额:$15.24万
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财政年份:1998
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SIGMA RECEPTOR SIGNALING IN FOCAL CEREBRAL ISCHEMIA
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批准号:6112203
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资助金额:$15.49万
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财政年份:1998
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负责人:JEFFREY R KIRSCH
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依托单位:
ROLE OF NITRIC OXIDE IN CEREBRAL BLOOD FLOW CONTROL IN CEREBRAL ISCHEMIA
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批准号:6243543
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项目类别:
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资助金额:$22.07万
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财政年份:1996
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负责人:JEFFREY R KIRSCH
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依托单位:
CEREBRAL ISCHEMIA AND FREE OXYGEN RADICALS
-
批准号:3084028
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项目类别:
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资助金额:$6.48万
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财政年份:1987
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负责人:JEFFREY R KIRSCH
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依托单位:
CEREBRAL ISCHEMIA AND FREE OXYGEN RADICALS
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批准号:3084030
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项目类别:
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资助金额:$7.43万
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财政年份:1987
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负责人:JEFFREY R KIRSCH
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依托单位:
CEREBRAL ISCHEMIA AND FREE OXYGEN RADICALS
-
批准号:3084031
-
项目类别:
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资助金额:$7.56万
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财政年份:1987
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负责人:JEFFREY R KIRSCH
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依托单位:
CEREBRAL ISCHEMIA AND FREE OXYGEN RADICALS
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批准号:3084032
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项目类别:
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资助金额:$7.92万
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财政年份:1987
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负责人:JEFFREY R KIRSCH
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依托单位:
CEREBRAL ISCHEMIA AND FREE OXYGEN RADICALS
-
批准号:3084029
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项目类别:
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资助金额:$7.47万
-
财政年份:1987
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负责人:JEFFREY R KIRSCH
-
依托单位:
Sigma Receptor Signaling in Focal Ischemia
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批准号:7553594
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项目类别:
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资助金额:$22.95万
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财政年份:--
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负责人:JEFFREY R KIRSCH
-
依托单位:
ROLE OF NITRIC OXIDE IN CEREBRAL BLOOD FLOW CONTROL IN CEREBRAL ISCHEMIA
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批准号:3782852
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:JEFFREY R KIRSCH
-
依托单位:
ROLE OF NITRIC OXIDE IN CEREBRAL BLOOD FLOW CONTROL IN CEREBRAL ISCHEMIA
-
批准号:5215168
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:JEFFREY R KIRSCH
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依托单位:--
Sigma Receptor Signaling in Focal Ischemia
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批准号:7553576
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项目类别:
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资助金额:$23.29万
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财政年份:--
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负责人:JEFFREY R KIRSCH
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依托单位:
Sigma Receptor Signaling in Focal Ischemia
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批准号:7553588
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项目类别:
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资助金额:$24.0万
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财政年份:--
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负责人:JEFFREY R KIRSCH
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依托单位:
Sigma Receptor Signaling in Focal Ischemia
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批准号:7553582
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项目类别:
-
资助金额:$23.78万
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财政年份:--
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负责人:JEFFREY R KIRSCH
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依托单位:
海外基金