Canonical Transient Receptor Potential Channels and Excitotoxicity

典型瞬时受体电位通道和兴奋性毒性

基本信息

批准号：
7895102
负责人：
FANG ZHENG
金额：
$ 36.25万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-16 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895102
关键词：
Acute Address Agonist Area Brain Calcium Calcium Channel Cations Cell Death Cessation of life Clinical Trials Coupled Craniocerebral Trauma D Aspartate Data Epilepsy Event Excitatory Amino Acid Antagonists Exposure to Family Family member Functional disorder Future G-Protein-Coupled Receptors GTP-Binding Proteins Gene Family Generations Genetic Glutamate Receptor Glutamates Goals Grant Hippocampus (Brain)In Vitro Ion Channel Knock-out Knockout Mice Knowledge Lateral Limbic System Link Medial Mediating Metabotropic Glutamate Receptors Modeling Molecular Target Mus Nerve Degeneration Neurons Neuroprotective Agents Neurotransmitters Pathway interactions Pattern Permeability Phospholipase C Pilocarpine Play Predisposition Propidium Diiodide RNA Interference Role Seizures Signal Pathway Signal Transduction Slice Staining method Stains Status Epilepticus Stroke Structure Subfamily lentivirinae Subgroup Testing abstracting base channel blockers drug development effective therapy excitotoxicity fluoro jade follow-up hippocampal pyramidal neuron in vivo in vivo Model nervous system disorder neuron loss novel protein distribution receptor receptor coupling research study response tool

项目摘要

(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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Critical role of canonical transient receptor potential channel 7 in initiation of seizures.

规范瞬态受体电位通道 7 在癫痫发作中的关键作用。

DOI：
发表时间：
2014-08-05
期刊：
影响因子：
11.1
作者：
Phelan, Kevin D;Shwe, U Thaung;Abramowitz, Joel;Birnbaumer, Lutz;Zheng, Fang
通讯作者：
Zheng, Fang

TRPC3 channels play a critical role in the theta component of pilocarpine-induced status epilepticus in mice.

TRPC3 通道在毛果芸香碱诱导的小鼠癫痫持续状态的 theta 成分中发挥关键作用。

DOI：
发表时间：
2017
期刊：
影响因子：
5.6
作者：
Phelan, Kevin D;Shwe, U Thaung;Cozart, Michael A;Wu, Hong;Mock, Matthew M;Abramowitz, Joel;Birnbaumer, Lutz;Zheng, Fang
通讯作者：
Zheng, Fang

Pilocarpine-induced status epilepticus in mice: A comparison of spectral analysis of electroencephalogram and behavioral grading using the Racine scale.

毛果芸香碱诱导的小鼠癫痫持续状态：脑电图频谱分析和使用拉辛量表的行为分级的比较。