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孩子的行为，记忆或学习能力的脑功能中的残疾有关。这种残疾对个人，家人以及社会造成了毁灭性的心理，情感和经济后果。残疾子集的分子碱基涉及包括NMDA受体（NMDAR）在内的各种离子通道家族中引起疾病的突变。由两个甘氨酸结合Glun1亚基组装而形成的阳离子选择性NMDAR通道和两个谷氨酸结合的Glun2亚基介导了一种缓慢的Ca2+可渗透性突触流的可刺激性成分，这些兴奋性突触电流可以触发突触强度的变化，一种学习的细胞易位。 NMDAR在正常的大脑发育中也起着重要作用。在过去的三年中，已经报道了大量突变（> 140），导致认为这些突变存在于神经系统疾病的一部分中，尤其是早期发作的疾病。令人惊讶的是，出现神经系统疾病的儿科患者中发现的NMDAR突变的发生率为5.7％，类似于或高于Na+，K+，Ca2+通道和GABA受体的NMDAR突变。在具有广泛神经发育问题的儿童中已经确定了NMDAR亚基的突变，包括注意力缺陷多动障碍（ADHD），自闭症谱系障碍，发育迟缓，精神降低，精神分裂症，智力残疾和可悲的癫痫发作。不幸的是，几乎没有对这些突变的功能分析，因此无法在临床表型中评估突变的影响。我们提出了4种实验线，以解决由NMDAR亚基突变引起的基于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）中突变的功能效应，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个突变的NMDAR亚基的受体，从而能够评估杂合患者的功能。目标1。TM链接区域中的人类NMDAR突变如何影响功能？我们将分析跨膜结构域或相关接头中的26个突变。我们将协作以获取开放频道配置的晶体的努力。目标2。配体结合域中的人NMDAR突变如何影响函数？我们将评估配体结合域中36个突变的功能效应，并协作以获取晶体学数据。目标3。人NMDAR突变如何影响神经元的运输和功能？我们将分析用突变NMDAR亚基转染的切片培养物中NMDAR介导的突触电流的性质。 AIM 4。NMDAR通道病可以治疗吗？我们将评估功能障碍NMDAR突变的FDA批准的NMDAR拮抗剂的效力（IC50），并评估NMDAR突变的神经毒性潜力。