AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

AMPA 受体泛素化和病理性突触过度兴奋

• 批准号: 10327201
• 负责人: Nien-Pei Tsai
• 金额: $ 5.94万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327201
• 关键词: AMPA Receptors; Award; Data; Epilepsy; Genetic Transcription; Hippocampus (Brain); In Vitro; Molecular; Neuraxis; Neuronal Plasticity; Neurons; Parents; Pathologic; Predisposition; Receptor Activation; Regulation; Role; Seizures; Synapses; TP53 gene; Training; Ubiquitination; Up-Regulation; comorbidity; disadvantaged background; excitatory neuron; graduate student; in vivo; metabotropic glutamate receptor type 1; nervous system disorder; neuronal excitability; novel

PROJECT SUMMARY/ABSTRACT Activation of group 1 (Gp1) metabotropic glutamate receptors leads to robust elevation of intrinsic excitability of hippocampal excitatory neurons. Abnormally elevated activity of Gp1 mGluR, on the other hand, has been observed in multiple neurological disorders with comorbid epilepsy. Despite these observations, the mechanisms underlying elevated intrinsic excitability and seizure activity following activation of Gp1 mGluRs remain unclear. Through the support of the parent award, our recent studies discovered that the activity of tumor suppressor p53 is positively correlated with neuronal excitability in vitro and seizure susceptibility in vivo. Because our latest data showed an up-regulation of p53 protein levels and transcription activity upon Gp1 mGluR activation, we hypothesize that activation of Gp1 mGluRs promotes neuronal intrinsic excitability and seizure activity in part through p53. In Aim 1, we propose to study the molecular regulation of p53 activity following activation of Gp1 mGluR. In Aim 2, we propose to determine the contribution of p53 to Gp1 mGluR-induced elevation of neuronal intrinsic excitability. In Aim 3, we propose to evaluate the role of p53 in Gp1 mGluR- associated seizure activity in vivo. We expect this project to (1) provide training to a promising graduate student who came from a disadvantaged background, (2) elucidate the mechanism underlying activation of Gp1 mGluR- induced neuronal hyperexcitability, which is within the scope of Aim 2.3 of the parent award; and (3) broaden our fundamental understanding of p53 in the central nervous system, which is directly associated with Aim 3.3 of the parent award.

项目概要/摘要 第 1 组 (Gp1) 代谢型谷氨酸受体的激活导致内在 海马兴奋性神经元的兴奋性。另一方面，Gp1 mGluR 活性异常升高， 已在多种伴有癫痫共病的神经系统疾病中观察到。尽管有这些观察结果， Gp1 mGluR 激活后内在兴奋性和癫痫活性升高的机制 仍不清楚。在家长奖的支持下，我们最近的研究发现，肿瘤的活性 抑制因子 p53 与体外神经元兴奋性和体内癫痫易感性呈正相关。 因为我们的最新数据显示 p53 蛋白水平和 Gp1 mGluR 转录活性上调 激活，我们假设 Gp1 mGluRs 的激活促进神经元内在兴奋性和癫痫发作 活动部分通过p53进行。在目标 1 中，我们建议研究 p53 活性的分子调控 Gp1 mGluR 的激活。在目标 2 中，我们建议确定 p53 对 Gp1 mGluR 诱导的贡献 神经元内在兴奋性升高。在目标 3 中，我们建议评估 p53 在 Gp1 mGluR- 中的作用 相关的体内癫痫发作活动。我们期望这个项目（1）为有前途的研究生提供培训 来自弱势背景的人，(2) 阐明 Gp1 mGluR- 激活的机制 诱发神经元过度兴奋，属于家长奖目标2.3的范围； (3) 扩大 我们对中枢神经系统中 p53 的基本了解，这与目标 3.3 直接相关 的家长奖。