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NMDAR Mutations & Neurodevelopmental Disorder: from Mechanism to Targeted Therapy

NMDAR 突变

基本信息

批准号：
10620814
负责人：
HONGJIE YUAN
金额：
$ 33.65万
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/10620814
关键词：
Address Animal Model 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 Histopathology Human Individual Intellectual functioning disability Ion Channel Gating Knock-in Knock-in Mouse Knock-out Knockout Mice Ligands Link Measures Mediating Memantine Modeling Morphology Mus Mutation N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neocortex Neurodevelopmental Disorder Neurodevelopmental Problem Neurologic Neurons Patients Permeability Pharmaceutical Preparations 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 pharmacologic postsynaptic 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.

摘要