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）是一种毁灭性的世界性疾病，被认为是世界上最严重的创伤性脑损伤。 到2020年，第三大最普遍的健康问题将导致患者死亡。人类大脑的创伤 由许多因素引起的极其困难的问题，包括：大脑复杂性，TBI多样性， 众多的细胞靶点，以及损伤的进行性。我们在动物中建立TBI模型的能力至关重要 用于开发治疗策略以最小化损伤和/或促进恢复。一个共同的特点， TBI，从震荡到穿透性损伤，是弥漫性和进行性的突触损伤， 导致功能丧失。我们的研究将在没有神经元损失的情况下模拟突触损伤， 海马检查的行动机制，基础上进行性突触损伤。我们假设 海马多巴胺能神经元的共递质D-丝氨酸的阶段性释放， 在调节突触功能中的重要作用;然而，损伤后，D-丝氨酸在神经元中受到抑制， 在星形胶质细胞中上调。星形胶质细胞D-丝氨酸紧张性释放增加导致亚致死性兴奋毒性突触 受伤后的第一周。我们还发现，星形胶质细胞D-丝氨酸水平的提高， 由三重突触中的神经元-星形胶质细胞通讯调节。具体来说，我们假设， 神经元ephrinB 3与星形胶质细胞EphB 3和EphA 4通讯以调节D-丝氨酸的产生， release. TBI后，反应性星形胶质细胞中Eph信号传导水平的增加导致TBI过度释放。 D-丝氨酸我们的研究采取全面的方法来解决我们的假设，使用尖端的 技术和细胞特异性敲除和敲入小鼠，以研究调节D-丝氨酸的机制， 介导的突触功能和功能障碍。