Potassium Channel Gene Therapy to Prevent Neuron Death

描述（来自申请人的逐字描述？摘要：虽然基因治疗已经 被证明是大脑中兴奋性毒性损伤的有希望的策略， 目前使用的载体在表达后不能足够快地表达功能性蛋白质。 损伤靶向坏死神经元损伤的最早事件阅读。这 一项提案测试了一种新的策略：潜在的 一种保护性蛋白质，其活性可被损伤激活。癫痫发作， 根据定义，兴奋毒性，减少这种兴奋可能是 神经保护这可能是通过超极化兴奋的神经元来实现的 通过向外整流钾（K+）通道，从而延长恢复 动作电位的相位和/或缩短尖峰持续时间。保护 将探索Ca 2+调节的或电压门控的K+通道的作用。在 我们的初步数据表明，在原代海马培养中， 抗谷氨酸盐星形孢菌素和氰化钠我们将把这些 通过测试更多的侮辱以及探索在多大程度上， 保护靶向坏死对凋亡。体内研究不仅 检查是否有神经元数量的节省，但功能也是如此 （使用电生理学和行为终点）。最后，我们将研究 这些通道在健康神经元中的活动，如果它们是活跃的， 对正常学习和记忆的影响。

DESCRIPTION (Verbatim from applicant?s abstract): Although gene therapy been shown to be a promising strategy for excitotoxic insults in the brain, currently used vectors do not express functional protein soon enough after insult to target the earliest events reading to necrotic neuronal injury. This proposal tests a novel strategy: constitutive expression of a potentially protective protein whose activity would be activated by insult. Seizures are, by definition, excitotoxic, and decreasing such excitation might be neuroprotective. This might be accomplished by hyperpolarizing excited neurons via outwardly rectifying potassium (K+) channels, thus prolonging the recovery phase of the action potential and/or shortening spike duration. The protective effects of a Ca2+-regulated or a voltage-gated K+ channel will be explored. In pilot data we have shown that both protect in primary hippocampal cultures against glutamate, staurosporine, and sodium cyanide. We will extend these findings by testing more insults as well as exploring the extent to which protection targets necrosis vs. apoptosis. In vivo studies will not only examine whether there is sparing of neuron number, but of function as well (using electrophysiological and behavioral endpoints). Finally, we will examine the activity of these channels in healthy neurons and, if they are active, test their effects on normal learning and memory.