Role of brain mechanosensors on outcome after traumatic brain injury

 描述(申请人提供)：找出为什么一些患者需要更长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，将显著提高我们识别脑损伤患者的能力，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亚基赋予受体一种“力感觉”特性，我们确定这一特性是由GluN2B受体亚基上的丝氨酸残基的磷酸化控制的。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机械敏感性是否提供了基于生物力学的原因来解释大脑对脑外伤的易感性和脆弱性？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脑损伤后将显示认知缺陷和神经元变性的显著减少。我们的建议从两个方面检验这一假说：目的1：检验GluN2B-S1323位点突变是否会影响神经发育、行为、海马体功能和神经结构。目的：研究GluN2B亚基突变的动物在实验性脑损伤后的预后是改善(NMDA1323A)还是恶化(NMDA1323E)。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“力感觉”能力显著降低，因此在轻度脑损伤后，它们的认知障碍明显减少，恢复更快。相反，NMDA1323E小鼠在脑损伤后将显示出更多的缺陷。影响：据我们所知，这项工作将第一次在分子水平上改变脑创伤的生物力学。我们预计这项工作会产生两个广泛的科学主题。首先，我们将研究增强GluN2B亚单位表达的表观遗传因素，使个体更容易受到脑外伤的影响。其次，我们将测试力敏感GluN2B亚单位的表达是否会使正在恢复的大脑更容易受到第二次损伤。

 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.