Glutamate receptors and human neurological disease

谷氨酸受体与人类神经系统疾病

基本信息

批准号：
9923776
负责人：
Stephen F Traynelis
金额：
$ 74.52万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9923776
关键词：
Address Agonist Alzheimer&apos s Disease Binding Binding Sites Biology Brain Cations Chemistry Clinical Collaborations Corpus striatum structure Cryoelectron Microscopy Development Disease Electrophysiology (science)Epilepsy Evaluation Gene Frequency Genes Genetic Genetic Variation Genome Glutamate Receptor Glutamates Human Individual Ion Channel Ischemia Learning Mediating Memory Molecular Structure Mutation N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neurologic Neuroprotective Agents Parkinson Disease Penetration Permeability Pharmaceutical Chemistry Pharmacology Population Probability Process Property Protein Region Rare Diseases Receptor Signaling Research Risk Factors Robotics Role Site Solubility Stroke Structure Synaptic Transmission Thalamic structure Therapeutic Variant design disorder risk experimental study genetic analysis improved in vivo in vivo Model insight interest nervous system disorder novel novel therapeutic intervention novel therapeutics postsynaptic precision medicine programs rare variant receptor receptor function side effect structural biology synaptic function tool treatment strategy

项目摘要

This R35 Research Program proposal will use electrophysiological, molecular, and structural approaches to probe multiple aspects of excitatory synaptic function that are relevant for neurological disease. We will focus on the elucidation and modulation of the functional properties of postsynaptic glutamate receptors. We will take advantage of coincident advances in cryoEM, genetics, robotics, and receptor biology to address questions that were previously inaccessible. Four approaches will address critical gaps in our understanding of synaptic function and provide therapeutically-relevant insight into neurological disease. First, we will explore the functional and clinical implications of regional intolerance for variation in the healthy population as well as de novo disease-associated glutamate receptor mutations, most commonly found in GRIN1, GRIN2A, GRIN2B, GRIN2D, genes that are among the least tolerant in the genome. We will establish the relationship in healthy individuals between allelic frequency and functional changes, which is necessary in order to understand the potential role of SNPs in these genes as disease risk factors. Evaluation of these rare variants will also provide opportunities for precision medicine, and advance our understanding of receptor function. Second, we will develop novel compounds for proof-of-concept studies to identify new therapeutic strategies for neurological disorders. We will synthesize subunit-selective modulators of agonist potency and channel open probability to assess the roles of understudied NMDA receptor subunits (e.g. GluN2C, GluN2D) in circuits in cortex, thalamus, and striatum. We will determine the site and mechanism of action of modulators of NMDA receptors, and use medicinal chemistry to improve brain penetration, potency, and solubility in collaboration with Dennis Liotta in Chemistry at Emory. We will use the pharmacological tools that we develop to gain insight into the treatment of epilepsy, stroke, Parkinson’s disease, and Alzheimer’s disease. Third, we explore biased modulators of NMDA receptors by developing the SAR of two classes of compounds that alter ion channel selectivity. These compounds represent the first example whereby a pharmacological agent can alter channel permeation properties, demonstrating that modulators can tune distinct functions of the NMDA receptor. These compounds hold enormous potential as neuroprotectants that diminish cation flux without side effects associated with receptor blockade, which we will evaluate in vivo in models of ischemia. Fourth, we will combine information obtained through genetic analysis of regional intolerance, mechanism of allosteric modulation, and new advances in structural biology to advance our understanding of the mechanisms that convert glutamate binding to channel opening. These experiments will focus on the shared regions of the protein that control channel opening, which are the key sites of action of our allosteric modulators and common sites for disease-associated human mutations. We will collaboratively perform cryoEM and crystallographic studies to determine the binding site for modulators, as well as key features of channel structure and function.

该 R35 研究计划提案将使用电生理学、分子和结构方法来我们将重点探讨与神经系统疾病相关的兴奋性突触功能的多个方面。我们将阐明和调节突触后谷氨酸受体的功能特性。利用冷冻电镜、遗传学、机器人技术和受体生物学的同步进步来解决以下问题以前无法实现的四种方法将解决我们对突触的理解中的关键差距。功能并提供对神经系统疾病的治疗相关的见解。首先，我们将探讨区域不耐受对健康人群变异的功能和临床影响。人群以及与疾病相关的谷氨酸受体突变，最常见于 GRIN1， GRIN2A、GRIN2B、GRIN2D，是基因组中耐受性最差的基因。健康个体中等位基因频率和功能变化之间的关系，这是为了了解这些基因中 SNP 作为疾病危险因素的潜在作用评估这些罕见变异。还将为精准医学提供机会，并增进我们对受体功能的理解。其次，我们将开发用于概念验证研究的新型化合物，以确定新的治疗策略我们将合成激动剂效力和通道开放的亚基选择性调节剂。评估正在研究的 NMDA 受体亚基（例如 GluN2C、GluN2D）在电路中的作用的概率我们将确定 NMDA 调节剂的作用位点和机制。受体，并利用药物化学来提高大脑的渗透性、效力和溶解度与埃默里大学化学系的 Dennis Liotta 合作，我们将使用我们开发的药理学工具来获得见解。治疗癫痫、中风、帕金森病和阿尔茨海默病。第三，我们通过开发两类化合物的 SAR 来探索 NMDA 受体的偏向调节剂这些化合物代表了药理学的第一个例子。剂可以改变通道渗透特性，证明调节剂可以调节通道的不同功能这些化合物作为减少阳离子通量的神经保护剂具有巨大的潜力。没有与受体阻断相关的副作用，我们将在缺血模型中进行体内评估。第四，我们将结合通过遗传分析获得的信息，对区域不耐受、机制进行分析。变构调节和结构生物学的新进展促进我们对其机制的理解将谷氨酸结合转化为通道开放这些实验将集中于共享区域。控制通道开放的蛋白质，这是我们的变构调节剂和常见的作用的关键位点我们将合作进行冷冻电镜和晶体学研究。研究确定调节剂的结合位点以及通道结构和功能的关键特征。