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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 癫痫是美国最普遍的神经系统疾病之一，目前影响超过250万人。 当前可用的抗癫痫药虽然有效，但具有副作用，并针对有限的机制。 探索新的机制或治疗癫痫的策略仍然是一项艰巨的任务。 神经肽的速素家族包括PESS P，Neurokinin A和Neurokinin b的速毒素。 然而，旋转金蛋白发挥癫痫活性的细胞和分子机制本质上是未知的。 我们有强大的初步数据，表明速素在海马多个突触下通过抑制突触前末端的延迟整流器K+通道的多种突触中释放谷氨酸释放。 使用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+释放的部分是物质p诱导的谷氨酸释放增加所必需的。 我们还证明，使用海马切片在picrototoxin诱导的癫痫发作模型中，速毒素显着增加了癫痫发作活性。 该项目的目的是确定速齿蛋白诱导的谷氨酸释放和癫痫活性增加的细胞和分子机制。 我们将检验以下假设：速氨酸介导的谷氨酸释放增加是其癫痫发作的原因。 特定的目标1将确定速素促进谷氨酸释放的详细离子机制。 我们将确定所涉及的延迟整流器K+通道的亚型。 特定的目标2将确定速气蛋白介导的谷氨酸释放促进的信号转导机制。 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，因此我们将确定蛋白激酶C在速氨酸诱导的谷氨酸释放中的增加中所涉及的同工型。 特定的目标3将确定速蛋白在癫痫发作中的作用和机制。 我们将测量癫痫发作诱导的速素释放的增加，以确定内源释放的速素在癫痫发作中的作用。 我们还将在海马切片中使用二毒素诱导的癫痫发作模型来识别速度激素诱导的癫痫发作促进作用的信号转导机制。