Canonical Transient Receptor Potential Channels and Excitotoxicity

典型瞬时受体电位通道和兴奋性毒性

• 批准号: 7741176
• 负责人: FANG ZHENG
• 金额: $ 34.58万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741176
• 关键词: Accounting; Acute; Address; Agonist; Animals; Applications Grants; Area; Boxing; Brain; Calcium; Calcium Channel; Cations; Cell Death; Code; Coupled; Coupling; Craniocerebral Trauma; Data; Epilepsy; Event; Excitatory Amino Acid Antagonists; Exposure to; Family; Family member; Functional disorder; Funding; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Generations; Genetic; Glutamate Receptor; Glutamates; Goals; Grant; Hand; Hippocampus (Brain); In Vitro; Injection of therapeutic agent; Ion Channel; Knock-out; Knockout Mice; Knowledge; Lateral; Limbic System; Link; Medial; Mediating; Metabotropic Glutamate Receptors; Minor; Modeling; Molecular Target; Mouse Strains; Mus; Nerve Degeneration; Neurons; Neuroprotective Agents; Neurotransmitters; Pathway interactions; Pattern; Pertussis Toxin; Pharmaceutical Preparations; Phase III Clinical Trials; Phospholipase C; Pilocarpine; Play; Predisposition; Propidium Diiodide; Pump; RNA Interference; Role; Seizures; Signal Transduction; Slice; Staining method; Stains; Status Epilepticus; Stroke; Structure; Subgroup; Testing; Time; abstracting; channel blockers; design; drug development; effective therapy; excitotoxicity; fluoro jade; follow-up; human embryonic stem cell; human subject; implantation; in vivo; in vivo Model; lateral ventricle; nervous system disorder; neuron loss; novel; protein distribution; public health relevance; receptor; receptor coupling; research study; response; tool

(revised abstract) Excitotoxicity plays a central role in the pathophysiology of epilepsy, stroke and head trauma. Overactivation of glutamate receptors leads to calcium overloading, triggering neuronal cell death. However, efforts to develop ionotropic glutamate receptor antagonists as neuroprotective agents have yet to be successful; alternative molecular targets for developing neuroprotective compounds need to be identified. Metabotropic glutamate receptors (mGluRs) are a family of G-protein coupled glutamate receptors. Group I mGluRs (mGluR1 and mGluR5) have been implicated in seizures and excitotoxicity. However, the underlying mechanism of excitotoxicity mediated by group I mGluRs is not known. The main hypothesis of this application is that group I mGluRs contribute to seizure and excitotoxicity by activating the canonical transient receptor potential (TRPC) channels, which is a subgroup of the TRP superfamily of non-selective cation channels. TRPC channels are identified as store-operated calcium channels (SOC) and are also activated by G-protein coupled receptors coupled to phospholipase C, such as group I mGluRs. Our preliminary data suggest that the TRPC1/4/5 subgroup of TRPCs, activated by group I mGluRs, play a critical role in the plateau potential underlying the epileptiform burst firing induced by group I mGluR agonists in the lateral septum, a limbic structure highly vulnerable to seizure-induced excitotoxicity. To follow up on this initial finding, Specific Aim 1 of this study will examine whether this plateau potential can be abolished by eliminating TRPC channels with TRPC channel blockers and by using a genetic knockout approach for specific TRPC channels. Specific Aim 1 will also determine whether there is a causal link between the mGluR-mediated plateau potential and acute excitotoxicity in the lateral septum. To determine whether TRPC channels contribute to seizure and excitotoxicity in vivo, the well-established pilocarpine- induced limbic seizure model will be used. Specific Aim 2 will test the hypothesis that TRPC1 and TRPC4 contribute to susceptibility to pilocarpine-induced seizures in vivo; and Specific Aim 3 will determine the distinct roles of TRPC1 and TRPC4 in neurodegeneration caused by pilocarpine-induced seizures in vivo. The long-term goal of this project is to elucidate the specific role of distinct TRPC family members in excitotoxicity. (description of abstract revision) The changes made to the abstract involve a deletion of all mention of experiments dealing with the use of the TRPC5(-/-) or TRPC1(-/-)/TRPC5(-/-) knockout mice. In addition, the signaling studies mentioned in the abstract have been deleted. All else has remained the same since the proposed experiments to remain in the grant address the original scope of the grant.

（修改后的摘要） 兴奋性毒性在癫痫、中风和头部的病理生理学中起着核心作用 创伤。谷氨酸受体过度激活导致钙超载，引发 神经元细胞死亡。然而，开发离子型谷氨酸受体的努力 拮抗剂作为神经保护剂尚未取得成功；替代分子 需要确定开发神经保护化合物的目标。代谢型 谷氨酸受体 (mGluR) 是 G 蛋白偶联谷氨酸受体家族。 I 组 mGluR（mGluR1 和 mGluR5）与癫痫发作和 兴奋性毒性。然而，I 组介导的兴奋性毒性的潜在机制 mGluR 尚不清楚。本申请的主要假设是 I 组 mGluR 通过激活经典瞬时受体导致癫痫发作和兴奋性毒性 潜在（TRPC）通道，它是非选择性 TRP 超家族的一个亚组 阳离子通道。 TRPC 通道被确定为钙池操纵的钙通道 (SOC) 并且也被与磷脂酶 C 偶联的 G 蛋白偶联受体激活，例如 作为 I 组 mGluR。我们的初步数据表明 TRPC1/4/5 亚组 由 I 组 mGluR 激活的 TRPC 在平台电位中发挥着关键作用 I 组 mGluR 激动剂在侧脑区诱发癫痫样爆发 隔膜，一种边缘结构，极易受到癫痫发作引起的兴奋性毒性的影响。关注 根据这一初步发现，本研究的具体目标 1 将检验这一平稳期是否 可以通过使用 TRPC 通道阻断器消除 TRPC 通道来消除潜力 以及针对特定 TRPC 通道使用基因敲除方法。具体目标 1 还将确定 mGluR 介导的平台之间是否存在因果关系 侧隔膜潜在的和急性的兴奋性毒性。判断是否TRPC 通道有助于体内癫痫发作和兴奋性毒性，公认的毛果芸香碱 将使用诱导边缘癫痫模型。具体目标 2 将检验以下假设： TRPC1 和 TRPC4 有助于体内对毛果芸香碱诱导的癫痫发作的易感性； 具体目标 3 将确定 TRPC1 和 TRPC4 在 由毛果芸香碱引起的体内癫痫发作引起的神经变性。长期目标是 该项目旨在阐明不同 TRPC 家族成员在 兴奋性毒性。 （摘要修订说明） 对摘要所做的更改涉及删除所有提及的实验 处理 TRPC5(-/-) 或 TRPC1(-/-)/TRPC5(-/-) 敲除小鼠的使用。在 此外，摘要中提到的信号研究已被删除。其他的都有 自从提议的实验保留在赠款中以来，一直保持不变 原来的资助范围。