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: 10447004
• 负责人: Noële Doreen Certain
• 金额: $ 1.08万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447004
• 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大脑的关键特征 功能。 AMPA受体调节与许多脑部疾病有关，包括药物成瘾，A 仅在美国就影响超过2000万患者的疾病。 AMPA受体是谷氨酸门控离子 负责学习和记忆过程的渠道以及失调可能导致加强 加性行为。 AMPA受体与不同的辅助亚基有关。这些辅助亚基 调节两个AMPA受体功能活性在突触上的表达。辅助亚基的机制 调节的AMPA受体表达知之甚少。我有初步数据，表明一类 辅助亚基，称为Cornichon同源物，调节AMPA受体组件，特别是从 受体二聚体成功能四聚体（AIM 1）。我将评估与相关的人类AMPA受体变体 神经发育障碍可能破坏辅助亚基相互作用并影响受体组件 （目标2）。为了评估受体生物发生和运输，我将通过双重标记AMPA采取一种新颖的方法 受体及其辅助亚基鉴定细胞内变化。我还将衡量突触的更改 由于AMPA受体的丧失 - 辅助亚基相互作用而导致的传播和可塑性。这些目标的结果 将提供有关AMPA受体的细胞内处理和治疗途径的见解 目标。我从F99阶段获得的神经生物学和获得的技术获得的知识对于 我过渡到神经科学的博士后位置。对于K00阶段，我计划在 实验室专注于体内电生理学和成像，以研究啮齿动物的药物成瘾过程 模型（目标3）。该提案的最终目标是学习创新技术以调查变化 分子和生物水平，并发展成为神经科学家的专业知识和独立性。