COBRE: UND: TACHYKININ MODULATION OF EPILEPSY

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 癫痫是美国最常见的神经系统疾病之一，目前影响超过250万人。 目前可用的抗癫痫药物，虽然有些有效，有副作用，并针对有限的机制。 探索治疗癫痫的新机制或策略仍然是一项艰巨的任务。 包括P物质、神经激肽A和神经激肽B的神经肽的速激肽家族是促惊厥的。 然而，速激肽发挥致癫痫活性的细胞和分子机制基本上尚不清楚。 我们有强有力的初步数据表明，速激肽显着增加谷氨酸释放在多个突触的海马通过抑制延迟整流钾通道突触前终端。 与敲除小鼠和药理学方法，我们也表明，磷脂酶C和蛋白激酶C的活动是完全的，而细胞内Ca 2+的释放是部分所需的P物质诱导的谷氨酸释放增加。 我们还表明，速激肽显着增加癫痫发作活动的印防己毒素诱导的癫痫发作模型，使用海马切片。 本项目的目的是确定详细的细胞和分子机制背后的速激肽诱导的谷氨酸释放和癫痫活动的增加。 我们将测试这一假设，即速激肽介导的谷氨酸释放的增加是负责其致癫痫活动。 具体目标1将确定详细的离子机制，速激肽促进谷氨酸释放。 我们将确定所涉及的延迟整流钾通道的亚型。 具体目标2将确定潜在的速激肽介导的促进谷氨酸释放的信号转导机制。 由于我们的初步数据表明，蛋白激酶C的活性是必不可少的，我们将确定参与速激肽诱导的谷氨酸释放增加的蛋白激酶C亚型。 具体目标3将确定速激肽在癫痫发作中的作用和机制。 我们将测量肾上腺素诱导的速激肽释放增加，以确定内源性释放的速激肽在癫痫发作中的作用。 我们还将使用印防己毒素诱导的癫痫发作模型在海马脑片，以确定潜在的速激肽诱导的癫痫发作活动的便利化的信号转导机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Epilepsy is one of the most prevalent neurological diseases in the USA, currently affecting more than 2.5 million individuals. The currently available antiepileptic drugs, while somewhat effective, have side effects and target a limited number of mechanisms. Exploring novel mechanisms or strategies to treat epilepsy is still an arduous task. The tachykinin family of neuropeptides that include substance P, neurokinin A and neurokinin B are proconvulsant. However, the cellular and molecular mechanisms whereby tachykinins exert epileptogenic activities are essentially unknown. We have strong preliminary data demonstrating that tachykinins dramatically increased glutamate release at multiple synapses of the hippocampus by inhibiting the delayed rectifier K+ channels at presynaptic terminals. With knock-out mice and pharmacological approaches, we have also shown that the activities of phospholipase C and protein kinase C were fully, whereas intracellular Ca2+ release was partially required for substance P-induced increases in glutamate release. We also demonstrated that tachykinins significantly increased seizure activities in a picrotoxin-induced seizure model using hippocampal slices. The objective of this project is to determine the detailed cellular and molecular mechanisms underlying tachykinin-induced increases in glutamate release and epileptogenic activities. We will test the hypothesis that tachykinin-mediated increases in glutamate release are responsible for their epileptogenic activities. Specific Aim 1 will identify the detailed ionic mechanisms by which tachykinins facilitate glutamate release. We will identify the subtype of the delayed rectifier K+ channels involved. Specific Aim 2 will identify the signal transduction mechanisms underlying tachykinin-mediated facilitation of glutamate release. Because our preliminary data indicated that the activity of protein kinase C was essential, we will determine the involved isoform of protein kinase C in tachykinin-induced increases in glutamate release. Specific Aim 3 will determine the roles and mechanisms of tachykinins in seizures. We will measure seizure-induced increase in the release of tachykinins to determine the roles of endogenously released tachykinins in seizure generation. We will also use the picrotoxin-induced seizure model in hippocampal slices to identify the signal transduction mechanisms underlying tachykinin-induced facilitation of seizure activities.