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-天冬氨酸接收器（NMDAR）是配体门控离子通道，介导慢兴奋后突触电流的成分，并在正常的大脑功能中起重要作用。遗传编码Glun亚基的笑基因的变化与神经发育障碍有关，包括癫痫性脑病，自闭症和智力障碍，这些残疾具有毁灭性的心理和对个人，家人和社会的经济后果。遵循有关疾病的第一份报告 - 在2010年引起笑容变种，已经鉴定出大量的人类变体（> 300）在患有各种神经系统问题的小儿患者中。我们在上一个资金周期中的研究表明类似的表型（即癫痫发作）可能是由于功能获得（GOF）和功能丧失变体引起的（LOF）在同一基因中。我们的工作还表明，不同的笑容变体对 FDA批准的药物，对三名无关患者的同一治疗有不同的反应在“ 1个”试验中托管相同的变体。拟议的实验将提供第一个详细评估 LOF和GOF NMDAR的电路功能在不同的发育阶段，并解决两者如何对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与异常活动相关的哪些电路连接，并将促进机会个性化医学，提出缓解功能变化的新治疗策略。特定目的1：对新确定的疾病相关的笑容变种的功能评估和评估 Grin2a普通人群中的变体。我们将分析所有新发布的功能属性和未发表的疾病相关的笑容变体在接收者的理解区域中。我们将确定健康个体中蛋白质功能与等位基因频率之间的关系，并评估不耐受基因变异的想法可以充当神经系统疾病的危险因素。特定目标2：NMDAR活动的丧失如何促进网络过度兴奋并诱导癫痫发作表型？我们将评估主持两种LOF变体和Glun2a敲除小鼠的体内敲除小鼠探索NMDAR功能的丧失是否会减少突触抑制并导致网络过度刺激性。特定目的3：功能获得的笑容变体相关的早期癫痫发作的机制是什么脑病？我们将在三个GOF笑变体中使用体内敲蛋白鼠标模型来确定增强的NMDAR功能是否驱动癫痫发作和早期发作的癫痫性脑病。特定目标4：如何最好地治疗笑容/nmdar的通道病？我们将筛选约2,000 fda- 批准的药物能够纠正笑容变体引起的过度兴奋性的能力。我们将评估 FDA批准的药物在转基因小鼠上，以确定是否可以恢复兴奋/抑制失衡。