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Stabilizing the tripartite synaptic complex following TBI

TBI 后稳定三方突触复合体

基本信息

批准号：
10844877
负责人：
Daniel Jon Liebl
金额：
$ 5.22万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10844877
关键词：
Acceleration Acute Address Affect Aging Agonist Alzheimer&apos s Disease Amino Acid Transporter Amino Acids Astrocytes Attention Brain Brain Injuries Cells Chronic Cognition Complex Conscious Dementia Dendritic Spines Disease Enzymes Event Female Flow Cytometry Foundations Functional disorder Gene Targeting Genetic Genetic Techniques Glycine High Pressure Liquid Chromatography Hippocampus Human Huntington Disease Imaging Techniques Immunohistochemistry Impaired cognition Injury Intervention Journals Knockout Mice Learning Link Long-Term Potentiation Mediating Memory Microglia Modeling Mus N-Methyl-D-Aspartate Receptors Natural regeneration Neurobiology Neurodegenerative Disorders Neuroglia Neurons Output Parkinson Disease Pathologic Pathology Patients Phase Physiologic pulse Play Process Production Recovery Recovery of Function Research Personnel Role Serine Signal Transduction Slice Source Synapses Synaptic Transmission Synaptic plasticity Therapeutic Tissues Traumatic Brain Injury Traumatic Brain Injury recovery Traumatic injury behavior test brain cell brain circuitry central nervous system injury clinical investigation cognitive function conditional knockout conditioned fear experimental study extracellular human model human tissue improved outcome interdisciplinary approach loris male morris water maze mouse model neural neurotransmission novel novel therapeutics parent grant pharmacologic response serine racemase synaptic function transcriptomics

项目摘要

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.

摘要：人类的意识和认知功能是由一个由神经组成的复杂的大脑回路控制的由集成的多蜂窝网络管理的连接。神经胶质细胞占大脑所有细胞的90%，并发挥作用在星形胶质细胞和小胶质细胞调节突触传递的神经元信号传递中动态和主动的作用和可塑性。在过去的十年中，越来越多的证据表明，N-甲基-D-的主要共同激动剂- 天冬氨酸受体(NMDAR)是D-氨基酸，D-丝氨酸，而不是甘氨酸；然而，很少有研究研究了其在中枢神经系统病理中的作用。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，其中三方突触内的胶质细胞独特地合成并释放D-丝氨酸病理性事件的发生。我们假设小胶质细胞是病理性D-丝氨酸的关键来源过度激活突触外NMDAR亚单位，启动小胶质细胞靶向和突触损伤修剪树枝状刺。我们提出的实验将检验(1)D-丝氨酸从小胶质细胞；(2)突触损伤和小胶质细胞靶向和修剪的机制；(3)转录分析在小鼠和人类模型中的脑损伤。我们将通过同时利用基因和脑损伤复杂性中小胶质细胞作用机制的药理学研究使用最先进的转录、成像和基因技术。我们的学习会带来更好的结果对调节突触损伤和功能障碍的机制的理解，也将开始定义用于患者干预的新疗法。