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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.

(修订摘要) 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。精神创伤。谷氨酸受体的过度激活导致钙超载，触发神经细胞死亡。然而，开发离子型谷氨酸受体的努力作为神经保护剂的拮抗剂尚未成功；替代分子需要确定开发神经保护化合物的目标。代谢性谷氨酸受体(MGluRs)是G蛋白偶联的谷氨酸受体家族。 I组mGluR(mGluR1和mGluR5)与癫痫和兴奋性毒性。然而，I组介导的兴奋性毒性的潜在机制 MGluRs尚不清楚。这一应用的主要假设是第I组mGluRs 通过激活规范的瞬时受体促进癫痫发作和兴奋性毒性潜在(TRPC)通道，是非选择性色氨酸超家族的一个子组阳离子通道。TRPC通道被认为是钙离子通道(SOC) 也被与磷脂酶C偶联的G蛋白偶联受体激活，如作为I组mGluRs。我们的初步数据表明，TRPC1/4/5亚组由I组mGluRs激活的TRPC在平台电位中起着关键作用 I组mGluR激动剂在外侧区诱发癫痫样放电的基础隔是一种边缘结构，非常容易受到癫痫诱发的兴奋性毒性的影响。追随在这一初步发现的基础上，这项研究的具体目标1将检查这种平台期可以通过使用TRPC通道阻滞剂消除TRPC通道来消除潜力并通过对特定的TRPC通道使用基因敲除方法。具体目标1 也将确定mGluR介导的平台之间是否存在因果联系外侧隔区的潜在和急性兴奋性毒性。要确定TRPC是否在体内，通道有助于癫痫发作和兴奋毒性，成熟的匹罗卡品- 将采用诱导边缘惊厥模型。《特定目标2》将检验这一假设 TRPC1和TRPC4在体内对匹罗卡品诱发癫痫的易感性有贡献；具体目标3将确定TRPC1和TRPC4在匹罗卡品致痫所致的神经变性。的长期目标是该项目旨在阐明不同的TRPC家族成员在兴奋性毒性。 (摘要修订说明) 对摘要所作的修改涉及删除所有提及实验的内容处理TRPC5(-/-)或TRPC1(-/-)/TRPC5(-/-)基因敲除小鼠的使用。在……里面此外，摘要中提到的信号研究已被删除。其他一切都有保持不变，因为拟议的实验仍保留在赠款地址中赠款的原始范围。