Auxiliary subunit regulation of AMPA receptor assembly and trafficking in health and disease

AMPA 受体组装和健康和疾病运输的辅助亚基调节

• 批准号: 10318453
• 负责人: Noële Doreen Certain
• 金额: $ 3.42万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318453
• 关键词: AMPA Receptors; Addictive Behavior; Address; Affect; American; Animal Model; Behavior; Biogenesis; Brain; Brain Diseases; Complex; Data; Development; Developmental Delay Disorders; Disease; Drug Addiction; Drug Exposure; Electrophysiology (science); Functional disorder; Glutamate Receptor; Goals; Health; Hippocampus (Brain); Human; Image; Intellectual functioning disability; Interruption; Ion Channel Gating; Knowledge; Laboratories; Lead; Learning; Link; Measures; Mediating; Memory; Missense Mutation; Modeling; Molecular; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurosciences; Patients; Pharmaceutical Preparations; Phase; Positioning Attribute; Process; Psychological reinforcement; Regulation; Research; Research Project Grants; Rewards; Rodent Model; Role; Signal Transduction; Slice; Substance abuse problem; Surface; Synapses; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Training; Transmembrane Domain; United States; Variant; Withdrawal; Work; addiction; autism spectrum disorder; base; dimer; effective therapy; experience; gel electrophoresis; in vivo; innovation; insight; novel; novel strategies; opioid epidemic; receptor; receptor expression; skills; synaptic function; targeted treatment; therapeutic development; therapeutic target; trafficking

PROJECT SUMMARY The regulation of the number and composition of AMPA receptors is a critical feature in maintaining brain function. AMPA receptor regulation has been implicated in numerous brain disorders including drug addiction, a disorder that affects more than 20 million patients in the US alone. AMPA receptors are glutamate-gated ion channels, responsible for the process of learning and memory, and dysregulation can lead to reinforcement of additive behaviors. AMPA receptors are associated with diverse auxiliary subunits. These auxiliary subunits regulate both AMPA receptor functional activity expression at synapses. Mechanisms of how auxiliary subunits regulate AMPA receptor expression are poorly understood. I have preliminary data indicating that a class of auxiliary subunits, called cornichon homologs, regulate AMPA receptor assembly, specifically the transition from receptor dimers into functional tetramers (Aim 1). I will evaluate human AMPA receptor variants associated with neurodevelopmental disorders that potentially disrupt auxiliary subunit interactions and affect receptor assembly (Aim 2). To evaluate receptor biogenesis and trafficking, I will take a novel approach by dual tagging AMPA receptors and their auxiliary subunits to identify intracellular changes. I will also measure changes to synaptic transmission and plasticity due to loss of AMPA receptor - auxiliary subunit interactions. Results from these aims will provide insights into the intracellular processing of AMPA receptors and potential avenues for therapeutic targets. The knowledge I gain in neurobiology and acquired techniques from the F99 Phase will be essential for my transition into a postdoctoral position in neuroscience. For the K00 Phase, I plan to pursue training in a laboratory focused on in vivo electrophysiology and imaging to investigate the process of drug addiction in rodent models (Aim 3). The ultimate goal of this proposal is to learn innovative techniques to investigate changes at the molecular and organismal level and to develop the expertise and independence to become an neuroscientist.

项目摘要 AMPA受体的数量和组成的调节是维持脑功能的关键特征， 功能AMPA受体调节与许多大脑疾病有关，包括药物成瘾， 这种疾病仅在美国就影响了2000多万患者。AMPA受体是谷氨酸门控离子 通道，负责学习和记忆的过程，和失调可导致加强 添加剂行为AMPA受体与不同的辅助亚基相关。这些辅助亚单位 调节AMPA受体在突触处的功能活性表达。辅助亚基 对AMPA受体表达的调控知之甚少。我有初步的数据表明， 辅助亚基，称为cornichon同系物，调节AMPA受体组装，特别是从 受体二聚体转化为功能性四聚体（Aim 1）。我将评估人类AMPA受体变异与 可能破坏辅助亚基相互作用并影响受体组装的神经发育障碍 (Aim 2）的情况。为了评估受体的生物发生和运输，我将采用一种新的方法， 受体及其辅助亚单位，以确定细胞内的变化。我也会测量突触的变化 由于AMPA受体-辅助亚基相互作用的丧失，导致了传递和可塑性的降低。这些目标的成果 将提供深入了解AMPA受体的细胞内加工和潜在的治疗途径， 目标的我从F99阶段获得的神经生物学知识和获得的技术将是必不可少的， 我在神经科学领域的博士后职位对于K 00阶段，我计划在 一个专注于体内电生理学和成像的实验室，以研究啮齿动物的药物成瘾过程 模型（目标3）。本提案的最终目标是学习创新技术，以调查 分子和有机体水平，并发展成为神经科学家的专业知识和独立性。