Stabilizing the tripartite synaptic complex following TBI

TBI 后稳定三方突触复合体

• 批准号: 10056316
• 负责人: Daniel Jon Liebl
• 金额: $ 5.87万
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056316
• 关键词: Address; Animals; Astrocytes; Brain; Brain Concussion; Cells; Communication; Complex; Diffuse; Disease; Eph Family Receptors; Functional disorder; Health; Hippocampus (Brain); Human; Injury; Knock-in Mouse; Knockout Mice; Mediating; Modeling; Mus; Nature; Neurons; Patients; Phase; Play; Production; Recovery; Role; Serine; Signal Transduction; Synapses; Techniques; Therapeutic; Trauma; Traumatic Brain Injury; cellular targeting; functional loss; mortality; neuron loss; novel; serine receptor; synaptic function

Summary: Traumatic brain injury (TBI) is a devastating worldwide disorder, and is believed to become the third most prevalent health concern contributing to patient mortality by 2020. Trauma to the human brain is an extremely difficult problem that arises from numerous factors including; brain complexity, TBI diversity, numerous cellular targets, and the progressive nature of the injury. Our ability to model TBI in animals is critical for developing therapeutic strategies to minimize damage and/or promote recovery. One common feature of TBI, ranging from concussive to penetrating injuries, is diffuse and progressive synaptic damage that ultimately leads to functional losses. Our studies will model synaptic damage in the absence of neuron losses in the hippocampus to examine mechanisms of action that underlie progressive synaptic damage. We hypothesize that the phasic release of the co-transmitter D-serine from hippocampal glutaminergic neurons plays an important role in regulating synaptic function; however, following injury D-serine is suppressed in neurons but up regulated in astrocytes. Increased tonic release of astrocytic D-serine leads to sub-lethal excititoxic synaptic damage over the first week post-injury. We have also found that enhanced astrocytic D-serine levels are regulated by neuronal-astrocyte communication in the tripartite synapse. Specifically, we hypothesize that neuronal ephrinB3 communicates with astrocytic EphB3 and EphA4 to regulate D-serine production and release. Following TBI, increased levels of Eph signaling in reactive astrocytes results in excessive release of D-serine. Our studies take a comprehensive approach to address our hypotheses using cutting edge techniques and cell specific knockout and knockin mice to investigate the mechanisms that regulate D-serine mediated synaptic function and dysfunction.

摘要：创伤性脑损伤（TBI）是一种毁灭性的全球障碍，被认为是 到2020年，最普遍的健康问题是导致患者死亡率的原因。人脑的创伤是 非常困难的问题来自许多因素，包括：大脑复杂性，TBI多样性， 许多细胞靶标以及损伤的渐进性。我们在动物中建模TBI的能力至关重要 制定治疗策略以最大程度地减少损害和/或促进康复。一个共同特征的一个 从脑震荡到穿透性伤害的TBI是弥漫性和进行性突触损害，最终是 导致功能损失。我们的研究将在没有神经元损失的情况下模拟突触损伤 海马检查是进行渐进突触损害的作用机制。我们假设 从海马谷氨酰胺能神经元中的共晶剂D-丝氨酸的阶段释放播放 在调节突触功能中的重要作用；但是，在受伤后，D链抑制在神经元中被抑制，但 在星形胶质细胞中调节。星形胶质细胞D-丝氨酸的补品释放增加导致亚致死性兴奋性突触 伤害后的第一周损坏。我们还发现，增强的星形胶质细胞D-丝氨酸水平是 由三方突触中的神经元 - 胃细胞通信调节。具体来说，我们假设 神经元Ephrinb3与星形胶质细胞EPHB3和EPHA4通信，以调节D-丝氨酸的产生和 发布。 TBI之后，反应性星形胶质细胞中EPH信号的水平升高导致过度释放 D-serine。我们的研究采用一种全面的方法来解决我们的假设使用尖端 技术和细胞特异性敲除和敲除小鼠，以研究调节D丝氨酸的机制 介导的突触功能和功能障碍。