Transcriptional Mechanism underlying Neuronal Hyperexcitability in FXS

FXS 神经元过度兴奋的转录机制

基本信息

批准号：
10746620
负责人：
Nien-Pei Tsai
金额：
$ 43.62万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10746620
关键词：
Acute Address Affect Anxiety Apoptosis Behavioral Cancer Biology Cell Cycle Clinical Trials Complex Data Defect Developmental Delay Disorders Disease model Dissociation Double Minutes Down-Regulation Epilepsy Exhibits FMR1 Female Fragile X Syndrome Future Gene Expression Genes Genetic Transcription Hippocampus Hypersensitivity In Vitro Inherited Intellectual functioning disability Intention Knock-out Knockout Mice Knowledge Measures Molecular Mus Neocortex Neuronal Differentiation Neurons Patients Phenotype Predisposition Prosencephalon Publishing Receptor Activation Regulation Reporting Research Research Priority Role Seizures Sensory Signal Transduction Slice Strategic Planning Synapses TP53 gene Testing Therapeutic United States National Institutes of Health Up-Regulation Work associated symptom audiogenic seizure autism spectrum disorder design effective therapy excitatory neuron improved in vivo inhibitor male metabotropic glutamate receptor type 1 mouse model multi-electrode arrays neocortical neuronal excitability novel novel therapeutics patch clamp pharmacologic response social anxiety transcription factor transcriptome sequencing ubiquitin-protein ligase

Acute Address Affect Anxiety Apoptosis Behavioral Cancer Biology Cell Cycle Clinical Trials Complex Data Defect Developmental Delay Disorders Disease model Dissociation Double Minutes Down-Regulation Epilepsy Exhibits FMR1 Female Fragile X Syndrome Future Gene Expression Genes Genetic Transcription Hippocampus Hypersensitivity In Vitro Inherited Intellectual functioning disability Intention Knock-out Knockout Mice Knowledge Measures Molecular Mus Neocortex Neuronal Differentiation Neurons Patients Phenotype Predisposition Prosencephalon Publishing Receptor Activation Regulation Reporting Research Research Priority Role Seizures Sensory Signal Transduction Slice Strategic Planning Synapses TP53 gene Testing Therapeutic United States National Institutes of Health Up-Regulation Work associated symptom audiogenic seizure autism spectrum disorder design effective therapy excitatory neuron improved in vivo inhibitor male metabotropic glutamate receptor type 1 mouse model multi-electrode arrays neocortical neuronal excitability novel novel therapeutics patch clamp pharmacologic response social anxiety transcription factor transcriptome sequencing ubiquitin-protein ligase

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项目摘要

PROJECT SUMMARY/ABSTRACT Fragile X syndrome (FXS) patients show multiple symptoms associated with neuronal, synaptic, and circuit hyperexcitability, such as sensory hypersensitivity, anxiety, and seizures. Although multiple mechanisms have been proposed to explain hyperexcitability in FXS, an effective treatment remains unavailable, indicating the need for search for more specific therapeutic strategy. It is well accepted that exaggerated activity of Group 1 metabotropic glutamate receptors (Gp1 mGluRs) contributes in part to the hyperexcitability in FXS. Activation of Gp1 mGluRs has been shown to lead to robust elevation of intrinsic excitability of hippocampal excitatory neurons and seizure susceptibility in mice. Despite these observations, the molecular regulation and mechanisms underlying elevated neuronal excitability following activation of Gp1 mGluRs have been complex and remain unclear. To improve our understanding of Gp1 mGluR-associated neuronal hyperexcitability in FXS, our preliminary observations led us to study the tumor suppressor p53. 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 data showed that activation of Gp1 mGluR leads to activation of p53, and the transcription activity of p53 is basally elevated in the FXS mouse model, the Fmr1 KO mice, we hypothesize that activation of Gp1 mGluR promotes neuronal intrinsic excitability in part through p53-dependent gene transcription, and inhibition of p53 can ameliorate neuronal excitability defects in FXS. To test this hypothesis, we propose in Aim 1 to study the mechanism by which p53 contributes to Gp1 mGluR activation-induced elevation of neuronal excitability. We will follow by pharmacologically or genetically inhibiting p53 in Aim 2 to determine whether the hyperexcitability phenotypes in Fmr1 KO mice can be ameliorated. We expect our research as proposed will provide a new aspect to our understanding of FXS. In addition, with the deep knowledge of p53 in the field of cancer biology and our preliminary data identifying neuron-enriched target genes of p53, the proposed research has the potential to introduce many new concepts into the design of future treatment for FXS.

项目摘要/摘要脆弱的X综合征（FXS）患者显示出多种症状，与神经元，突触和电路有关过度兴奋的性，例如感觉超敏反应，焦虑和癫痫发作。尽管多种机制具有提议解释FXS中的过度兴奋性，有效的治疗仍然不可用，表明需要寻找更具体的治疗策略。夸大了第1组的活动是很高兴的代谢性谷氨酸受体（GP1 mGlurs）部分促进了FXS的过度兴奋性。激活 GP1 mGlurs已显示可导致海马兴奋性内在兴奋性的强大升高小鼠的神经元和癫痫发作易感性。尽管有这些观察，但分子调节和 GP1 mglurs激活后神经元兴奋性升高的机制已经复杂并保持不清楚。为了提高我们对FXS中与GP1 MGLUR相关的神经元过度兴奋性的理解，我们的初步观察使我们研究了肿瘤抑制p53。我们最近的研究发现肿瘤抑制p53的活性与体外和癫痫敏感性的神经元兴奋性呈正相关体内。因为我们的数据表明，GP1 mglur的激活导致p53的激活，而转录在FXS小鼠模型（FMR1 KO小鼠）中，p53的活性基本上升高，我们假设激活的激活 GP1 mGlur通过p53依赖性基因转录部分促进了神经元的内在兴奋性，并且 p53的抑制可以改善FXS中神经元兴奋性缺陷。为了检验这一假设，我们提出了目标 1研究p53有助于GP1 MGLUR激活诱导的神经元升高的机制兴奋性。我们将遵循AIM 2中的药理或遗传抑制p53的p53，以确定是否是否可以改善FMR1 KO小鼠中的过度兴奋性表型。我们希望我们的研究按照拟议的意愿为我们对FXS的理解提供了一个新的方面。此外，在p53领域的深入了解癌症生物学和我们识别p53的神经元增强靶基因的初步数据，拟议的研究有潜力将许多新概念引入FXS的未来治疗设计。