Stabilizing the Tripartite Synaptic Complex Following TBI

TBI 后稳定三方突触复合体

• 批准号: 10581933
• 负责人: Daniel Jon Liebl
• 金额: $ 56.64万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581933
• 关键词: Acceleration; Acute; Address; Aging; Agonist; Alzheimer' s Disease; Amino Acid Transporter; Amino Acids; Astrocytes; Attention; Autopsy; Behavior; Brain; Brain Injuries; Cells; Cellular Structures; Cognition; Cognitive; Complement; Complex; Conscious; Dementia; Dendritic Spines; Electrophysiology (science); Event; Functional disorder; Gene Targeting; Genetic; Genetic Techniques; Glycine; Human; Huntington Disease; Imaging Techniques; Impaired cognition; Injury; Intervention; Link; Mediating; Mediator; Microdialysis; Microglia; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neuroglia; Neurons; Nuclear RNA; Parkinson Disease; Pathologic; Pathology; Patients; Phase; Play; Process; Research Personnel; Rodent; Role; Serine; Source; Synapses; Synaptic Transmission; Synaptic plasticity; Tissues; Translating; Traumatic Brain Injury; Traumatic injury; United States National Institutes of Health; behavior measurement; brain cell; brain circuitry; central nervous system injury; cognitive function; experimental study; extracellular; high resolution imaging; human model; human tissue; in vivo; injured; interdisciplinary approach; laser capture microdissection; mouse model; neural; neurotransmission; novel; novel therapeutics; pharmacologic; preservation; response; transcriptome sequencing; transcriptomics; translational potential

Summary: Human consciousness and cognitive function are governed by a complex brain circuitry made up of neural connections regulated by an integrated multicellular network. Glial make up 90% of all cells in the brain and play dynamic and active roles in neuronal signaling, where astrocytes and microglia regulate synaptic transmission and plasticity. In the past decade, increasing evidence suggests that the principal co-agonist for N-methyl-D- Aspartate receptors (NMDARs) is the D-amino acid, D-serine, rather than glycine; however, few studies have examined its role in CNS pathologies. To address this gap, we have recently identified a novel mechanism of synaptic damage, where glia within the tripartite synapse uniquely synthesize and release D-serine following the onset of pathological events. We hypothesize that microglia are a key source of pathological D-serine that hyperactivates extrasynaptic NMDAR subunits to initiate synaptic damage as a result of microglia targeting and pruning of dendritic spines. Our proposed experiments will examine (1) the mechanisms of D-serine release from microglia; (2) the mechanisms of synaptic damage and microglia targeting & pruning; (3) transcriptomic analysis of brain injury in both murine and human models. We will achieve this by employing both genetic and pharmacological approaches to dissect the mechanism of microglial action within the complexity of brain injury using state-of-the-art transcriptomic, imaging, and genetic techniques. Our studies will result in a better understanding of the mechanisms that regulate synaptic damage and dysfunction, but also will start to define novel therapeutics for patient interventions.

总结： 人类的意识和认知功能由一个复杂的大脑回路控制， 连接由一个综合的多细胞网络调节。神经胶质细胞占大脑所有细胞的90%， 在神经元信号传导中的动态和积极作用，其中星形胶质细胞和小胶质细胞调节突触传递 和可塑性。在过去的十年中，越来越多的证据表明，N-甲基-D- 天冬氨酸受体（NMDAR）是D-氨基酸，D-丝氨酸，而不是甘氨酸;然而，很少有研究表明， 研究了其在CNS病理学中的作用。为了解决这一差距，我们最近发现了一种新的机制， 突触损伤，其中三重突触内的胶质细胞独特地合成并释放D-丝氨酸， 病理事件的发生。我们假设小胶质细胞是病理性D-丝氨酸的关键来源， 超活化突触外NMDAR亚单位以引发作为小胶质细胞靶向的结果的突触损伤， 修剪树突棘。我们提出的实验将研究（1）D-丝氨酸释放的机制， （2）突触损伤机制和小胶质细胞靶向修剪机制;（3）转录组学分析 在小鼠和人类模型中的脑损伤。我们将通过使用遗传和 在复杂脑损伤中剖析小胶质细胞作用机制的药理学方法 使用最先进的转录组成像和遗传技术我们的研究将使我们的国家 了解调节突触损伤和功能障碍的机制，也将开始定义 用于患者干预的新疗法。