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K + EFFLUX--ROLE IN CA++ HOMEOSTASIS AND EXCITOTOXICITY

K + EFFLUX--ROLE IN CA++ HOMEOSTASIS AND EXCITOTOXICITY
K EFFLUX--CA 稳态和兴奋性毒性的作用
批准号:
2762014
负责人:
LECH Kiedrowski
金额:
$10.65万
依托单位国家:
美国
项目类别:
财政年份:
1999
资助国家:
美国
项目状态:
已结题
起止时间:
1999-01-01 至 2003-12-31

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中文摘要
翻译
在脑缺血的2-3分钟内, ([K+])。达到60 - 80 mM,这意味着, 在缺血期间谷氨酸在高度升高的[K+]o下被执行。 的 拟议的研究将研究这种高[K+]O是否会影响机制 谷氨酸兴奋性毒性假设“高[K+]O降低了 电化学钙驱动力(ECDF)在神经元暴露于 谷氨酸受体激动剂”将在目标1:“研究 不同[K+]o对质膜电位(Em)的影响, 培养皮层细胞胞浆Ca ~(2+)浓度([Ca ~(2+)]c), 暴露于谷氨酸受体激动剂的小脑神经元”。 本 最后,神经元将负载Em-和Ca 2 +-敏感的荧光 probes. 这一假设,如果是真的,预测高[K+]O可能会阻止 通过减少谷氨酸介导的跨膜Ca 2+内流, 质膜。 然而,谷氨酸也可能 使血浆中的Na+和K+浓度梯度崩溃 膜,因此,无论[K+]o如何,都将Em设置为接近零。 为了验证这一点,细胞质中的Na+和K+ 浓度将在神经元中的平行实验中测量 装载Na+和K+敏感的荧光探针。 一个替代 假设,将在目标2中进行检验:“确定增加[K+]o 可能抑制谷氨酸介导的Ca 2+内流, 到质膜去极化”。 为此, [K+]o对谷氨酸受体激动剂刺激的Ca 2+蓄积的影响 将在由Na+和K+离子载体去极化的神经元中进行研究, 短杆菌肽 最后,在目标3中:“测试是否恢复低[K+]o 体外缺血后引起延迟的Ca 2+积累, “损害神经元存活”,将研究[K+]o是否在 缺血后时期影响Ca 2+稳态,并与 在接下来的24小时内改善或损害神经元存活。 这些研究可能为药物干预提供新的靶点 为了减少局部缺血或低血糖后的神经元死亡,即, 以防止再灌注期间大脑中的K+过度流失。
英文摘要
Within only 2-3 min of brain ischemia, extracellular K+ concentrations ([K+])o reach 60 - 80 mM, which implies that the excitotoxic action of glutamate during ischemia is executed at highly elevated [K+]o. The proposed research will study whether such high [K+]o affects mechanisms of glutamate excitotoxicity. The hypothesis "High [K+]o reduces the electrochemical Ca2+ driving force (ECDF) in neurons exposed to glutamate receptor agonists" will be tested in Aim 1: "Study the effects of various [K+]o on the plasma membrane potential (Em) and the cytoplasmic Ca2+ concentration ([Ca2+]c) in cultured cortical and cerebellar neurons exposed to glutamate receptor agonists". To this end, neurons will be loaded with Em- and Ca2+-sensitive fluorescent probes. This hypothesis, if true, predicts that high [K+]o may prevent excitotoxicity by decreasing the glutamate mediated Ca2+ influx across the plasma membrane. It is also possible, however, that glutamate may collapse the Na+ and K+ concentration gradients across the plasma membrane and, consequently, set Em close to zero regardless of [K+]o. To test whether this is the case, the cytoplasmic Na+ and K+ concentrations will be measured in parallel experiments in neurons loaded with Na+- and K+-sensitive fluorescent probes. An alternative hypothesis, will be tested in Aim 2: "Determine whether increasing [K+]o may inhibit the glutamate-mediated Ca2+ influx in a manner not related to the plasma membrane depolarization". To this end, the effects of [K+]o on Ca2+ accumulation stimulated by glutamate receptor agonists will be studied in neurons depolarized by a Na+ and K+ ionophore, gramicidin. Finally, in Aim 3: "Test whether restoration of low [K+]o following ischemia in vitro causes a delayed Ca2+ accumulation and compromises neuronal survival", it will be studied whether [K+]o during the postischemic period affects Ca2+ homeostasis and is related to improved or compromised neuronal survival during the next 24 hours. These studies may yield a new target for pharmacological intervention to decrease neuronal death following ischemia or hypoglycemia, namely, to prevent excessive K+ loss from the brain during reperfusion.
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Cryopreserved preparations of male and female brain cells to study gender-related issues
  • 批准号:
    10080448
  • 项目类别:
  • 资助金额:
    $25.2万
  • 财政年份:
    2020
  • 负责人:
    LECH Kiedrowski
  • 依托单位:
Nigrostriatal co-cultures with dopaminergic neurons carrying a fluorescent tag
Mechanisms and implications of intracellular Zn2+ release in acidified neurons
Mechanisms and implications of intracellular Zn2+ release in acidified neurons
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