NMDAR Mutations & Neurodevelopmental Disorder: from Mechanism to Targeted Therapy

NMDAR 突变

基本信息

批准号：
9212171
负责人：
HONGJIE YUAN
金额：
$ 32.37万
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 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212171
关键词：
Address Affect Agonist Attention deficit hyperactivity disorder Binding Brain Cations Cell surface Child Child Behavior Communication Complementary DNA Complex Crystallization DNA Sequence Alteration Data Dependence Development Developmental Delay Disorders Dextrorphan Disease Dissociation Economics Emotional Epilepsy Evaluation FDA approved Family GABA Receptor Glutamates Glycine Hippocampus (Brain)Human Incidence Individual Induced Mutation Inherited Intellectual functioning disability Ion Channel Ketamine Knockout Mice Knowledge Learning Ligand Binding Domain Ligands Mediating Memantine Memory Mental Retardation Molecular Mus Mutation Mutation Analysis N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor A1 NMDA receptor antagonist Neurodevelopmental Disorder Neurodevelopmental Problem Neurologic Neurons Patients Permeability Pharmaceutical Preparations Pharmacology Play Property Protons Psyche structure Publishing Receptor Gene Reporting Role Running Schizophrenia Seizures Selective Serotonin Reuptake Inhibitor Series Site Slice Small Interfering RNA Societies Structural Models Structure Synapses System Testing Time Transmembrane Domain Tricyclic Antidepressive Agents Xenopus oocyte autism spectrum disorder base channel blockers clinical phenotype disability disease-causing mutation early onset experimental study gain of function gain of function mutation human disease knock-down molecular dynamics mutant nervous system disorder neuron development neurosteroids neurotoxic patient subsets pediatric patients personalized medicine public health relevance receptor receptor function targeted treatment trafficking virtual voltage

项目摘要

DESCRIPTION (provided by applicant): Neurodevelopmental disorders are associated with disabilities in brain function that affect a child's behavior, memory or ability to learn. Such disabilities carry devastating mental, emotional, and economic consequences for the individuals, their families, as well as society. The molecular bases for a subset of disabilities involve disease-causing mutations in various ion channel families, including NMDA receptors (NMDARs). The cation-selective NMDAR channels formed from assembly of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits mediate a slow, Ca2+-permeable component of excitatory synaptic currents that can trigger changes in synaptic strength, a cellular correlate of learning. NMDARs also play an important role in normal brain development. A large number of mutations (>140) have been reported in just the last three years, leading to the view that these mutations are present in a subset of patients with neurological disorders, particularly early onset intractable seizures. Surprisingly, the incidence of NMDAR mutations found in pediatric patients presenting with neurological problems is 5.7%, similar to or higher than that for Na+, K+ , Ca2+ channels and GABA receptors. Mutations in NMDAR subunits have been identified in children with a broad range of neurodevelopmental problems, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, developmental delay, mental retardation, schizophrenia, intellectual disability, and intractable seizures. Unfortunately, virtually no functional analysis of these mutations exists, making it impossible to evaluate effects of mutations in the context of clinical phenotype. We proposed 4 lines of experimentation addressing the molecular mechanism underlying neurological diseases suggested to arise from mutations in NMDAR subunits. We will study the functional effects of mutations in the transmembrane domain (TM), linkers, and ligand binding domains (LBD) and test the ability of FDA-approved drugs to rectify the mutation-induced gain-of-function. All experiments will utilize receptors that contain 0, 1, or 2 mutant NMDAR subunits, enabling an assessment of function in heterozygous patients. Aim 1. How do human NMDAR mutations in the TM- linker regions impact function? We will analyze 26 mutations in the transmembrane domain or associated linkers. We will collaborate on efforts to obtain crystals of the open channel configuration. Aim 2. How do human NMDAR mutations in the ligand binding domains impact function? We will evaluate the functional effects of 36 mutations in the ligand binding domain, and collaborate to obtain crystallographic data. Aim 3. How do human NMDAR mutations influence neuronal trafficking and function? We will analyze the properties of NMDAR-mediated synaptic current in slice cultures transfected with mutant NMDAR subunits. Aim 4. Are NMDAR channelopathies treatable? We will evaluate the potency (IC50) of FDA-approved NMDAR antagonists at gain-of-function NMDAR mutations and evaluate the neurotoxic potential of NMDAR mutations.

描述（由申请人提供）：神经发育障碍与影响儿童行为、记忆或学习能力的大脑功能障碍有关。这些残疾给个人、他们的家庭以及社会带来毁灭性的精神、情感和经济后果。部分残疾的分子基础涉及各种离子通道家族的致病突变，包括 NMDA 受体 (NMDAR)。阳离子选择性 NMDAR 通道由两个甘氨酸结合 GluN1 亚基和两个谷氨酸结合 GluN2 亚基组装而成，介导兴奋性突触电流的缓慢、Ca2+可渗透成分，可触发突触强度的变化，突触强度是学习的细胞相关性。 NMDAR 在正常大脑发育中也发挥着重要作用。仅在过去三年中就报道了大量突变（> 140），因此人们认为这些突变存在于神经系统疾病患者的子集中，特别是早发性顽固性癫痫发作。令人惊讶的是，在出现神经系统问题的儿科患者中发现的 NMDAR 突变发生率为 5.7%，与 Na+、K+、Ca2+ 通道和 GABA 受体相似或更高。 NMDAR 亚基突变已在患有多种神经发育问题的儿童中被发现，包括注意力缺陷多动障碍 (ADHD)、自闭症谱系障碍、发育迟缓、智力迟钝、精神分裂症、智力障碍和顽固性癫痫发作。不幸的是，实际上不存在对这些突变的功能分析，因此无法在临床表型的背景下评估突变的影响。我们提出了 4 条实验线，解决了由 NMDAR 亚基突变引起的神经系统疾病的分子机制。我们将研究跨膜结构域 (TM)、接头和配体结合结构域 (LBD) 突变的功能影响，并测试 FDA 批准的药物纠正突变诱导的功能获得的能力。所有实验都将利用包含 0、1 或 2 个突变 NMDAR 亚基的受体，从而能够评估杂合患者的功能。目标 1. 人类 NMDAR TM 连接区突变如何影响功能？我们将分析跨膜结构域或相关连接子中的 26 个突变。我们将共同努力获得开放通道配置的晶体。目标 2. 配体结合域中的人类 NMDAR 突变如何影响功能？我们将评估配体结合域中 36 个突变的功能影响，并合作获得晶体学数据。目标 3. 人类 NMDAR 突变如何影响神经元运输和功能？我们将分析转染突变 NMDAR 亚基的切片培养物中 NMDAR 介导的突触电流的特性。目标 4. NMDAR 通道病可以治疗吗？我们将评估 FDA 批准的 NMDAR 拮抗剂对功能获得性 NMDAR 突变的效力 (IC50)，并评估 NMDAR 突变的神经毒性潜力。