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：
10392917
负责人：
Stephen F Traynelis
金额：
$ 76.81万
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/10392917
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 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，分子和结构方法来探测与神经系统疾病有关的兴奋突触功能的多个方面。我们将重点关注突触后谷氨酸受体的功能特性的阐明和调节。我们会接受的冷冻，遗传学，机器人技术和受体生物学的一致性进步的优势，以解决问题以前是无法访问的。四种方法将解决我们对突触的理解的关键差距功能并提供与神经系统疾病的热相关的见解。首先，我们将探讨区域摄入剂对健康变化的功能和临床意义种群以及从头疾病相关的谷氨酸受体突变，最常见于Grin1， grin2a，grin2b，grin2d，是基因组耐受性最低的基因。我们将建立健康个体之间的关系，在shillic频率和功能变化之间，这是必要的了解SNP在这些基因中的潜在作用是疾病危险因素。评估这些稀有变体还将为精密医学提供机会，并提高我们对受体功能的理解。其次，我们将开发新的化合物概念证明研究，以确定新的治疗策略神经系统疾病。我们将合成激动剂效力的亚基选择调节器，并打开通道评估可理解的NMDA受体亚基（例如Glun2c，Glun2d）在电路中的作用的概率皮质，丘脑和纹状体。我们将确定NMDA调节剂的作用位点和机理受体，并使用药物化学来改善脑渗透，效力和可溶性协作与丹尼斯·利奥塔（Dennis Liotta）一起在埃默里（Emory）的化学中。我们将使用开发的药物工具来获得洞察力癫痫，中风，帕金森氏病和阿尔茨海默氏病的治疗。第三，我们通过开发两类化合物的SAR来探索NMDA受体的偏置调节剂改变离子通道的选择性。这些化合物代表了药理学的第一个例子代理可以改变通道渗透属性，表明调节器可以调整不同的功能 NMDA受体。这些化合物具有减少阳离子通量的神经保护剂的巨大潜力没有与接收器封锁相关的副作用，我们将在缺血模型中评估体内。第四，我们将通过遗传分析区域摄入术，机制，结合获得的信息变构调节以及结构生物学的新进步，以提高我们对机制的理解那将谷氨酸结合到通道开口。这些实验将集中于控制通道开放的蛋白质，这是我们的变构调节剂的关键作用部位与疾病相关的人类突变的部位。我们将协作进行冷冻和晶体学研究确定调制器的结合位点以及通道结构和功能的关键特征。