Human GRIA variants and neurological diseases: from molecular mechanism to rescue pharmacology

人类 GRIA 变异与神经系统疾病：从分子机制到救援药理学

基本信息

批准号：
10458777
负责人：
HONGJIE YUAN
金额：
$ 23.48万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458777
关键词：
AMPA Receptors Acids Address Affect Agonist Behavior Biological Assay Brain Bulla Cell Surface Receptors Cell Survival Cells Clinical Communication Complementary DNA Complex Data Disease Economics Emotional Epilepsy Evaluation FDA approved Family Fluorescence Microscopy GRIA3 gene Genes Genetic Variation Glutamates Hippocampus (Brain)Human Individual Inherited Intellectual functioning disability Intervention Ion Channel Ion Channel Gating Knowledge Learning Ligands Location Luciferases Mammalian Cell Measures Mediating Memory Molecular Morphology Mutation Neurodevelopmental Disorder Neurodevelopmental Problem Neurologic Symptoms Neurons Patients Pattern Pharmaceutical Preparations Pharmacology Play Population Property Psyche structure Publishing RNA Splicing Reporting Role Running Schizophrenia Series Societies Surface Swelling Synapses Synaptic Transmission Testing Time Variant Vertebral column Xenopus oocyte antagonist autism spectrum disorder beta-Lactamase channel blockers clinically relevant disability exome sequencing experimental study extracellular gain of function genome-wide human disease inhibitor insight kainate loss of function nervous system disorder neuron development neuropsychiatric disorder neuropsychiatry neurotoxicity neurotransmission novel novel therapeutic intervention personalized medicine positive allosteric modulator prevent receptor receptor function response targeted treatment trafficking virtual

项目摘要

Modified SUMMARY-ABSTRACT Neuropsychiatric disorders are associated with disabilities of brain function that affect individual’s behavior, memory and ability to learn. Such disabilities can carry devastating mental and economic consequences for the individuals, their families, and society. The molecular basis of a subset of these disabilities involves monogenic channelopathies, a term used to describe disease-causing variants in various ion channels. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), ligand-gated ion channels, represent tetrameric complexes comprised of varying combinations of four subunits, GluA1-4 (encoded by GRIA1-4). AMPARs mediate the fast component of excitatory post-synaptic currents. Patterns of AMPAR activation can trigger a change in synaptic strength, which is widely considered to be a cellular correlate of learning and memory, and play an important role in neuronal development. Following the first report on a disease-causing AMPAR variant in 2007, a large number of human variants (>200) scattered across four AMPAR subunits have been identified in patients with various neurodevelopmental and neuropsychiatric problems, including autism and intellectual disability. It has been suggested that GRIA2 and GRIA3 genes have genome-wide significance for autism and schizophrenia, respectively. Despite the rapid advance in identification of new variants, there are neither virtually no systematic functional analyses for the variants nor any evaluation of possible treatment options for the patients. We propose a series of functional and pharmacological experiments that will fill this gap in our knowledge and will determine the mechanisms underlying the effects of 64 disease-associated GRIA2 and GRIA3 variants that do not exist in healthy population. The proposed experiments will explore how the receptor and neuronal function is impacted by genetic changes in AMPAR GRIA genes. The results of our pharmacological experiments assessing the effects of FDA-approved drugs on AMPARs with patient-specific variants will advance opportunities for personalized medicine by suggesting new therapeutic strategies for mitigation of functional changes by these variants. Our data will also provide novel functional insight into the AMPAR function. Aim 1. How do human GRIA variants impact receptor function? We assess the effect of 64 missense GRIA2 and GRIA3 variants on agonist potency, time course of current responses, and cell surface receptor trafficking. Aim 2. How do human GRIA variants influence neuronal function? We will assess neuronal synapse number, spine morphology, trafficking locations (synaptic vs extrasynaptic), spontaneous mEPSCs, and the ability of induced neurotoxicity (cell viability as well as dendritic swelling) by a set of GRIA2 and GRIA3 variants. Aim 3. How can AMPAR channelopathies best be treated? For the gain-of-function variants, we will measure the IC50 for competitive antagonists, negative allosteric modulators, or channel blockers (including FDA-approved). We will estimate the EC50 for positive modulators (e.g. ampakines) for the loss-of-function variants.

修改后的摘要-摘要神经精神疾病与影响个人行为、记忆和学习能力的大脑功能障碍有关，这种障碍可能会给个人、他们的家庭和社会带来毁灭性的精神和经济后果。这些障碍的分子基础涉及单基因。通道病，用于描述各种离子通道中引起疾病的变异的术语。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）、配体门控离子通道、由四个亚基的不同组合组成的四聚体复合物，GluA1-4（由 AMPAR 编码）介导兴奋性突触后电流的快速成分，这被广泛认为是导致突触强度变化的原因。继 2007 年首次报道导致疾病的 AMPAR 变异后，大量研究发现它是学习和记忆的细胞相关因素，并在神经元发育中发挥着重要作用。已在患有各种神经发育和神经精神问题（包括自闭症和智力障碍）的患者中发现了分散在四个 AMPAR 亚基中的人类变异（>200）。有人认为 GRIA2 和 GRIA3 基因分别对自闭症和精神分裂症具有全基因组意义。尽管新变异的识别取得了快速进展，但实际上既没有对变异进行系统的功能分析，也没有对患者可能的治疗方案进行任何评估，我们提出了一系列功能和药理学实验来填补这一空白。我们的知识并将确定健康人群中不存在的 64 种与疾病相关的 GRIA2 和 GRIA3 变异的影响机制。拟议的实验将探索我们的 AMPAR GRIA 基因的遗传变化如何影响受体和神经元功能。评估 FDA 批准的药物对具有患者特异性变异的 AMPAR 的影响的药理学实验将通过提出减轻这些变异的功能变化的新治疗策略来促进个性化医疗的机会，我们的数据还将提供对 AMPAR 功能的新功能见解。目标 1. 人类 GRIA 变体如何影响受体功能？我们评估 64 种错义 GRIA2 和 GRIA3 变体对激动剂效力、当前反应的时间过程和细胞表面受体运输的影响。目标 2. 人类 GRIA 变异如何影响神经元功能？我们将评估神经元突触数量、脊柱形态、运输位置（突触与突触外）、自发性 mEPSC 以及诱导神经毒性的能力（细胞活力以及树突肿胀）。 GRIA2 和 GRIA3 变体集。目标 3. 如何最好地治疗 AMPAR 通道病？对于功能获得性变体，我们将测量竞争性拮抗剂、负变构调节剂或通道阻滞剂（包括 FDA 批准的）的 IC50。我们将估计正的 EC50。用于功能丧失变体的调节剂（例如 ampakines）。