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（由申请人提供）：找到一些患者需要更长的时间才能从轻度创伤性脑损伤（TBI）中恢复的确切原因，以及为什么一些大脑更容易受到快速头部旋转或撞击的影响，将显着提高我们识别 TBI 危险人群的能力，并帮助患者安全地从这些损伤中恢复。我们过去的工作表明，NMDA 受体的 GluN2B 亚基赋予受体“力感应”特性，并且我们确定该特征是通过 GluN2B 受体亚基上丝氨酸残基的磷酸化来控制的。我们利用这些过去的发现来提出一个广泛的问题——基于 GluN2B 的 NMDAR 机械敏感性是否为大脑对 TBI 的易感性和脆弱性提供了基于生物力学的原因？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 NMDAR 机械敏感性降低的转基因动物在单次和重复 TBI 后认知缺陷和神经元变性将显着减少。我们的提案通过两个目标检验这一假设： 目标 1：测试 GluN2B-S1323 位点突变是否影响神经发育、行为、海马功能和神经结构。目标 2：研究 GluN2B 亚基突变的动物在实验性 TBI 后是否表现出改善 (NMDA1323A) 或更差 (NMDA1323E) 的结果。我们预计 NMDAM1323A 和 NMDA1323E 小鼠将正常发育并表现出正常的认知功能。然而，由于 NMDA1323A 小鼠的“力感应”能力显着降低，因此在轻度 TBI 后，它们的认知缺陷将显着减少，并且恢复速度更快。相反，NMDA1323E 小鼠在 TBI 后会表现出增强的缺陷。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外伤生物力学的工作。我们预计这项工作会出现两个广泛的科学主题。首先，我们将研究增强 GluN2B 亚基表达的表观遗传因素，使个体更容易受到 TBI 的影响。其次，我们将测试力敏感 GluN2B 亚基的表达是否会使正在恢复的大脑更容易受到二次损伤。