NMDAR Mutations & Neurodevelopmental Disorder: from Mechanism to Targeted Therapy

NMDAR 突变

基本信息

批准号：
10388107
负责人：
HONGJIE YUAN
金额：
$ 33.2万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10388107
关键词：
Address Animal Model Body Weight decreased Brain Child Data Dendritic Spines Development Disease Drug Receptors Economics Electroencephalography Engineering Epilepsy Evaluation FDA approved Family Funding Gene Frequency General Population Genes Genetic Variation Genome Glutamate Receptor Hippocampus (Brain)Histopathology Human Individual Intellectual functioning disability Ion Channel Gating Knock-in Knock-in Mouse Knock-out Knockout Mice Lead Ligands Link Measures Mediating Memantine Modeling Morphology Mus Mutation N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neurodevelopmental Disorder Neurodevelopmental Problem Neurologic Neurons Patients Permeability Pharmaceutical Preparations Pharmacology Phenotype Play Prognosis Property Psyche structure Publishing Pyramidal Cells Reporting Resolution Risk Factors Role Seizures Signal Transduction Slice Societies Survival Rate Symptoms Synapses Synaptic Transmission Testing Thick Time Transgenic Mice Variant Work autism spectrum disorder de novo mutation defined contribution density early onset epileptic encephalopathies experimental study extracellular gain of function human disease in vivo loss of function mouse model neocortical nervous system disorder neuronal circuitry novel strategies novel therapeutic intervention pediatric patients personalized medicine precision medicine protein function rare variant receptor receptor function response synaptic inhibition targeted treatment

项目摘要

ABSTRACT N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that mediate the slow component of excitatory post-synaptic currents and play important roles in normal brain function. Genetic variations in GRIN genes, which encode the GluN subunits, are linked to neurodevelopmental disorders, including epileptic encephalopathy, autism, and intellectual disability, which carry devastating mental and economic consequences for the individuals, their families, and society. Following the first report on disease- causing GRIN variants in 2010, a large number of human variants (>300) in GRIN genes have been identified in pediatric patients with various neurologic problems. Our studies in the previous funding cycle indicated that similar phenotypes (i.e. seizures) could result from both gain-of-function (GoF) and loss-of-function variants (LoF) in the same gene. Our work also revealed that different GRIN variants present differential sensitivity to FDA-approved drugs, and there are divergent responses to the same treatment among three unrelated patients hosting the same variant in “N of 1” trials. The proposed experiments will provide the first detailed evaluation of circuit function following LoF and GoF NMDAR at different developmental stages, and address how the two opposite effects on NMDARs might generate a similar phenotype. These studies will define a critical window in which circuit connections relevant for aberrant activity are established, and will advance opportunities for personalized medicine by suggesting new therapeutic strategies for mitigation of functional changes. Specific Aim 1: Functional assessment of newly identified disease-associated GRIN variants and evaluation of GRIN2A variants in the general population. We will analyze the functional properties of all newly published and unpublished disease-associated GRIN variants in the understudied regions of the receptors. We will determine the relationship between protein function and allelic frequency in healthy individuals, and evaluate the idea that variation of intolerant genes can act as risk factors for neurological disorders. Specific Aim 2: How does the loss of NMDAR activity promote network hyperexcitability and induce epileptic phenotypes? We will evaluate in vivo knockin mice hosting two LoF variants and GluN2A knockout mice to explore whether loss of NMDAR function reduces synaptic inhibition and leads to network hyperexcitability. Specific Aim 3: What is the mechanism of gain-of-function GRIN variant-associated early-onset epileptic encephalopathy? We will use in vivo knockin mouse models for three GoF GRIN variants to determine whether enhanced NMDAR function drives seizures and early-onset epileptic encephalopathy. Specific Aim 4: How can GRIN/NMDAR channelopathies best be treated? We will screen ~2,000 FDA- approved drugs for their ability to rectify GRIN variant-induced hyperexcitability. We will evaluate actions of FDA-approved drugs on transgenic mice to determine if the excitation/inhibition imbalance can be restored.

抽象的 N-甲基-D-天冬氨酸受体 (NMDAR) 是配体门控离子通道，介导缓慢的兴奋性突触后电流的组成部分，在正常脑功能中发挥重要作用。编码 GluN 亚基的 GRIN 基因的变异与神经发育障碍有关，包括癫痫性脑病、自闭症和智力障碍，这些疾病会带来毁灭性的精神和在第一份关于疾病的报告之后，给个人、他们的家庭和社会带来了经济后果。 GRIN变异 2010年，大量人类GRIN基因变异（>300个）已被鉴定我们在上一个资助周期中的研究表明，患有各种神经系统问题的儿科患者。类似的表型（即癫痫发作）可能是由功能获得（GoF）和功能丧失变异引起的我们的工作还表明，不同的 GRIN 变体对同一基因表现出不同的敏感性。 FDA批准的药物，三名不相关的患者对相同的治疗有不同的反应在“N of 1”试验中托管相同的变体。拟议的实验将提供第一个详细的评估。 LoF 和 GoF NMDAR 在不同发展阶段的电路功能，并说明两者如何对 NMDAR 的相反影响可能会产生类似的表型，这些研究将定义一个关键窗口。建立了哪些与异常活动相关的电路连接，并将促进通过提出减轻功能变化的新治疗策略来进行个性化医疗。具体目标 1：新发现的与疾病相关的 GRIN 变异的功能评估和评估我们将分析所有新发表的 GRIN2A 变体的功能特性。我们将研究未发表的与疾病相关的 GRIN 受体未研究区域的变异。确定健康个体的蛋白质功能和等位基因频率之间的关系，并评估不耐受基因的变异可以作为神经系统疾病的危险因素。具体目标2：NMDAR活性丧失如何促进网络过度兴奋并诱发癫痫我们将评估携带两种 LoF 变体的体内敲入小鼠和 GluN2A 敲除小鼠探讨 NMDAR 功能的丧失是否会减少突触抑制并导致网络过度兴奋。具体目标3：功能获得性GRIN变异相关早发性癫痫的机制是什么我们将使用三种 GoF GRIN 变体的体内敲入小鼠模型来确定 NMDAR 功能增强是否会导致癫痫发作和早发性癫痫性脑病。具体目标 4：如何最好地治疗 GRIN/NMDAR 通道病？我们将筛选约 2,000 个 FDA- 因能够纠正 GRIN 变异引起的过度兴奋而获得批准的药物，我们将评估其作用。 FDA 批准的药物用于转基因小鼠，以确定是否可以恢复兴奋/抑制失衡。