Role of brain mechanosensors on outcome after traumatic brain injury

 描述（由申请人提供）：找到一些患者从轻度创伤性脑损伤（TBI）中恢复需要更长时间的确切原因以及一些大脑更容易受到快速头部旋转或撞击的原因，将显著提高我们识别TBI的at-rsk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GluN 2B亚基赋予受体“力感”特性，我们确定这一特征是由GluN 2B受体亚基上丝氨酸残基的磷酸化控制的。我们使用这些过去的研究结果提出了一个广泛的问题-基于GluN 2B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，我们假设具有降低的NMDAR机械敏感性的转基因动物在单次和重复TBI后将显示认知缺陷和神经元变性的显著降低。我们的建议在两个目标中检验这一假设：目标1：检测GluN 2B-S1323位点突变是否影响神经发育、行为、海马功能和神经结构。目的2：研究具有GluN 2B亚基突变的动物在实验性TBI后是否表现出改善的（NMDA 1323 A）或更差的（NMDA 1323 E）结果。我们预计NMDAM 1323 A和NMDA 1323 E小鼠将正常发育并表现出正常的认知功能。然而，由于它们具有显著降低的“力感”能力，NMDA 1323 A小鼠在轻度TBI后将显示出显著更少的认知缺陷和更快的恢复。相反，NMDA 1323 E小鼠在TBI后将显示增强的缺陷。影响：据我们所知，这项工作将首次在分子水平上改变脑创伤的生物力学。我们期望从这项工作中产生两个广泛的科学主题。首先，我们将定位于检查增强GluN 2B亚基表达的表观遗传因素，从而使个体更容易受到TBI的影响。其次，我们将测试力敏感GluN 2B亚基的表达使恢复中的大脑更容易受到第二次损伤的可能性。

 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.