COBRE: UND: TACHYKININ MODULATION OF EPILEPSY

COBRE：UND：速激肽对癫痫的调节

• 批准号: 7720880
• 负责人: Saobo Lei
• 金额: $ 23.12万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720880
• 关键词: Adverse effects; Affect; Antiepileptic Agents; Chromosome Pairing; Computer Retrieval of Information on Scientific Projects Database; Data; Epilepsy; Family; Funding; Generations; Glutamates; Grant; Hippocampus (Brain); Individual; Institution; Knockout Mice; Measures; Mediating; Modeling; Molecular; Neurokinin A; Neurokinin B; Neuropeptides; Numbers; Phospholipase C; Picrotoxin; Potassium Channel; Presynaptic Terminals; Protein Kinase C; Research; Research Personnel; Resources; Role; Seizures; Signal Transduction; Slice; Source; Substance P; Synapses; Tachykinin; Testing; United States National Institutes of Health; citrate carrier; nervous system disorder; novel

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 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在一定程度上有效，但具有副作用并且针对的机制有限。 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 在内的神经肽速激肽家族具有促惊厥作用。 然而，速激肽发挥致癫痫活性的细胞和分子机制基本上是未知的。 我们有强有力的初步数据表明，速激肽通过抑制突触前末端的延迟整流 K+ 通道，显着增加海马多个突触的谷氨酸释放。 通过敲除小鼠和药理学方法，我们还表明磷脂酶 C 和蛋白激酶 C 的活性是完全的，而细胞内 Ca2+ 的释放是 P 物质诱导的谷氨酸释放增加的部分需要。 我们还证明，在使用海马切片的印防己毒素诱导的癫痫发作模型中，速激肽显着增加了癫痫发作活动。 该项目的目的是确定速激肽诱导谷氨酸释放和致癫痫活性增加的详细细胞和分子机制。 我们将检验以下假设：速激肽介导的谷氨酸释放增加是其致癫痫活性的原因。 具体目标 1 将确定速激肽促进谷氨酸释放的详细离子机制。 我们将识别所涉及的延迟整流器 K+ 通道的子类型。 具体目标 2 将确定速激肽介导的谷氨酸释放促进背后的信号转导机制。 因为我们的初步数据表明蛋白激酶 C 的活性至关重要，所以我们将确定速激肽诱导的谷氨酸释放增加中所涉及的蛋白激酶 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。 我们将测量癫痫发作引起的速激肽释放增加，以确定内源性释放的速激肽在癫痫发作发生中的作用。 我们还将在海马切片中使用印防己毒素诱导的癫痫发作模型来确定速激肽诱导的癫痫发作活动促进背后的信号转导机制。