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GluN2D in Development and Disease

GluN2D 在发育和疾病中的作用

基本信息

批准号：
10704178
负责人：
HOWARD I SIROTKIN
金额：
$ 7.65万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704178
关键词：
Address Affect Alleles Birth Brain Child Clinical Data Defect Development Developmental Delay Disorders Developmental Process Disease DsRed Epilepsy Equilibrium Etiology Event Foundations Frameshift Mutation Functional disorder Genes Glutamates Goals Human Immunohistochemistry Ion Channel Gating Larva Learning Life Ligands Measures Mediating Mediator Membrane Memory Missense Mutation Modeling Morphology Mutation N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neurodevelopmental Disorder Neurotransmitters Pathogenicity Pathology Pattern Permeability Play Predisposition Process Prosencephalon Repression Role Seizures Social Behavior Synaptic Transmission System Testing Transgenic Organisms Variant Work Zebrafish autism spectrum disorder autistic clinical phenotype developmental disease effective therapy epileptic encephalopathies excitatory neuron experimental study gain of function human disease inhibitory neuron insight loss of function nerve stem cell nervous system disorder neurodevelopment neurogenesis neurotransmission novel prime editing receptor function stem

项目摘要

PROJECT SUMMARY/ABSTRACT NMDA receptors (NMDARs) are ligand-gated ion channels that are activated by glutamate, the principle excitatory neurotransmitter of the brain. Missense mutations in NMDAR subunits are associated with multiple neurodevelopmental disorders including autism, epilepsy and morphological anomalies. Nevertheless, it is unclear how particular functional alterations produce disease, especially as both gain and loss of function alleles have been identified with the same disorders. This proposal uses zebrafish as a model to explore the developmental roles of the understudied GluN2D subunit, which is associated with a severe neurological disorder, Developmental and Epileptic Encephalopathy (DEE). Based on novel preliminary data that shows NMDARs repress forebrain neurogenesis, we hypothesize that GluN2D dysfunction alters early neurogenesis and the subsequent balance of excitatory and inhibitory neurons. We propose two aims to test this premise. In Aim 1 we will determine the effects of complete loss of GluN2D on neurogenesis to establish a foundation for understanding the pathogenic impacts of GluN2D disease variants. In Aim 2 we will generate zebrafish models harboring DEE-associated GluN2D variants to directly assess their effects on neurogenesis. This work will provide new insights into the role of GluN2D in early development and establish a scalable strategy to interrogate the pathogenic mechanisms produced disease associated NMDAR variants that result in autism, epilepsy, and other neurodevelopmental disorders.

项目总结/摘要 NMDA受体（NMDAR）是由谷氨酸激活的配体门控离子通道，大脑的主要兴奋性神经递质。NMDAR亚基中的错义突变是与多种神经发育障碍相关，包括自闭症、癫痫和形态异常然而，目前还不清楚特定的功能改变如何影响产生疾病，特别是因为功能等位基因的获得和丧失都已被确定为同样的紊乱。这项提案使用斑马鱼作为模型，以探索发展中的作用，研究不足的GluN 2D亚基，与严重的神经系统疾病有关，发育性和癫痫性脑病（DEE）。根据新的初步数据，显示NMDAR抑制前脑神经发生，我们假设GluN 2D功能障碍改变早期神经发生和随后兴奋性和抑制性神经元的平衡。我们提出两个目标来检验这个前提。在目标1中，我们将确定完全丧失 GluN 2D对神经发生的影响，为理解 GluN 2D疾病变体。在目标2中，我们将生成斑马鱼模型， GluN 2D变体，以直接评估其对神经发生的影响。这项工作将提供新的深入了解GluN 2D在早期开发中的作用，并建立可扩展的策略，询问产生疾病相关NMDAR变体的致病机制，导致自闭症、癫痫和其他神经发育障碍。