Role of brain mechanosensors on outcome after traumatic brain injury

脑机械传感器对脑外伤后预后的作用

• 批准号: 8953344
• 负责人: DAVID F MEANEY
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8953344
• 关键词: Acute; Adult; Affect; Animals; Architecture; Area; Behavior; Biomechanics; Brain; Cognitive deficits; Development; Ensure; Epigenetic Process; Exhibits; Goals; Head; Hippocampus (Brain); Histological Techniques; Incidence; Individual; Injury; Lateral; Learning; Link; Liquid substance; Measures; Mechanics; Modeling; Molecular; Mus; Mutate; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurons; Neurophysiology - biologic function; Outcome; Patients; Pattern; Percussion; Phosphorylation; Population; Populations at Risk; Positioning Attribute; Predisposition; Property; Public Health; Recovery; Relative (related person); Research; Risk; Role; Rotation; Serine; Site; Slice; Stretching; Technology; Testing; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; Work; base; cognitive function; enhancing factor; improved; insight; mild traumatic brain injury; neurobehavior; neurodevelopment; public health relevance; receptor; research study; response; sensor; tool

 DESCRIPTION (provided by applicant): Finding precise reasons why some patients take much longer to recover from a mild traumatic brain injury (TBI) and why some brains are more vulnerable to rapid head rotation or impact will significantly improve our ability to identify at-rsk populations for TBI and help patients safely recover from these injuries. Our past work showed us the GluN2B subunit of the NMDA receptor confers a `force sensing' property to the receptor, and we determined this feature is controlled by phosphorylation of a serine residue on the GluN2B receptor subunit. We use these past findings to ask a broad question - does the GluN2B-based NMDAR mechanosensitivity provide a biomechanics-based reason for susceptibility and vulnerability of the brain to TBI? Our goal in this R21 proposal is to develop the transgenic tools to answer this question. To this end, we hypothesize that transgenic animals with reduced NMDAR mechanosensitivity will show a significant reduction in cognitive deficits and neuronal degeneration after both a single and repeated TBI. Our proposal examines this hypothesis in two aims: Aim 1: To test if GluN2B-S1323 site mutation affects neural development, behavior, hippocampal function, and neural architecture. Aim 2: To study if animals with mutations in the GluN2B subunit show improved (NMDA1323A) or worse (NMDA1323E) outcome after experimental TBI. We expect NMDAM1323A and NMDA1323E mice will develop normally and exhibit normal cognitive functions. However, because they have significantly reduced `force sensing' ability, NMDA1323A mice will show significantly less cognitive deficits and faster recovery after mild TBI. Conversely, NMDA1323E mice will show enhanced deficits following TBI. Impact: To our knowledge, this work will be the first to change the biomechanics of brain trauma at the molecular level. We expect two broad scientific themes emerging from this work. First, we would be positioned to examine epigenetic factors that enhance the expression of the GluN2B subunit, lending individuals more susceptible to TBI. Second, we would test the possibility that expression of the force-sensitive GluN2B subunit makes the recovering brain more vulnerable to a second injury.

 描述（由适用提供）：找到一些精确的原因，为什么某些患者需要更长的时间才能从轻度的脑损伤（TBI）中恢复过来，以及为什么某些大脑更容易受到快速旋转或影响的影响，这将显着提高我们识别TBI的AT-RSK人群并帮助患者从这些伤害中恢复过来的能力。我们过去的工作向我们展示了NMDA受体的Glun2b亚基，承认了受体的“力敏感性”特性，我们确定该特征是通过Glun2b受体亚基上的丝氨酸住宅磷酸化控制的。我们使用这些过去的发现来提出一个广泛的问题 - 基于Glun2b的NMDAR机制敏感性是否为基于生物力学的理由提供了易感性和大脑对TBI的脆弱性的原因？我们在R21提案中的目标是开发转基因工具来回答这个问题。为此，我们假设具有NMDAR机制降低的转基因动物将显示出一个单一和重复的TBI后认知缺陷和神经元变性的显着降低。我们的提案考试以两个目的为目标：目标1：测试GLUN2B-S1323位点突变是否影响神经元发展，行为，海马功能和神经元结构。目的2：研究在Glun2b亚基中具有突变的动物是否表现出改善（NMDA1323A）或更糟的（NMDA1323E）在实验性TBI后结果。我们预计NMDAM1323A和NMDA1323E小鼠将正常发展并暴露正常认知功能。但是，由于它们显着降低了“力敏感性”能力，因此NMDA1323A小鼠在轻度TBI后表现出明显较小的认知缺陷和更快的恢复速度。相反，NMDA1323E小鼠将在TBI后显示出增强的缺陷。影响：据我们所知，这项工作将是第一个在分子水平上改变脑创伤的生物力学的工作。我们预计这项工作会出现两个广泛的科学主题。首先，我们将定位检查增强Glun2b亚基表达的表观遗传因子，借出更容易受到TBI影响的个体。其次，我们将测试对力敏感的Glun2b亚基的表达使恢复大脑更容易受到第二损伤的可能性。