Biomechanical Analysis of Traumatic Brain Injury Models

这是一个竞争性的继续应用程序，重点是创伤性脑损伤模型的生物力学分析。 在上一个项目期间，我们确定了血管损伤和创伤性轴索损伤的机械阈值。虽然这些原发性神经病理学变化很重要，但它们仅代表创伤期间发生的事件的一小部分。在本项目期间，我们的长期目标是确定区分体内凋亡和坏死细胞死亡的局部机械应力条件，并测量不同脑区神经元和凋亡细胞死亡的机械耐受性变化。 我们的叠加假设是，细胞凋亡的机械阈值低于坏死细胞死亡阈值，并且皮质和海马存在不同的机械阈值。 我们进一步提出，近端机制的细胞溶质钙引起的阈值水平的细胞凋亡和坏死的机械拉伸的立即变化是不同的。研究的具体目标如下：（1）使用体内模型和有限元模拟来测量体内神经元凋亡和坏死的机械阈值，（2）计算跨两个脑区域-皮层和海马-的神经元中凋亡和坏死变化的相对体外机械阈值，（3）探讨在机械性坏死和凋亡条件下引起神经元钙内流的机制。通过实现研究计划的目标，我们希望将描述受伤时大脑区域变形的“机械应力图”转移到“细胞反应图”，预测受伤期间生物力学力发生的细胞变化区域。一旦完成，该研究将显著增强对现有模型的解释，以了解部分分子后遗症，进而了解闭合性头部损伤的治疗策略。

This is a competing continuation application that focuses on the biomechanical analysis of traumatic brain injury models. In the last project period, we identified the mechanical thresholds for vascular damage and traumatic axonal injury. Although significant, these primary neuropathological changes represent only a fraction of the events that occur during trauma. In this project period, our long term objective is determine the local mechanical stress conditions that distinguish apoptotic and necrotic cell death in vivo, and to measure the change in mechanical tolerance for both neuronal and apoptotic cell death across different brain regions. Our overlying hypothesis is that the mechanical threshold for apoptosis is below the necrotic cell death threshold, and that different mechanical thresholds exist for the cortex and hippocampus. We propose further that the proximal mechanisms for immediate shifts in cytosolic calcium caused at the threshold levels for apoptosis and necrosis by mechanical stretch are distinct. The specific aims of the research are as follows: (1) to measure the mechanical thresholds for in vivo neuronal apoptosis and necrosis using an in vivo model and finite element simulation, (2) to calculate the relative in vitro mechanical thresholds for apoptotic and necrotic changes in neurons across two brain regions - the cortex and the hippocampus, and (3) determine the mechanisms of calcium influx in neurons caused under the mechanical conditions of necrosis and apoptosis. By accomplishing the aims of the research plan, we expect to transfer 'mechanical stress maps' that describe the regional deformations of the brain that occur at the moment of injury to 'cellular response maps' that predict the areas of cellular changes occurring from the biomechanical forces during injury. Once accomplished, the research will significantly enhance the interpretation of existing models to understand a portion of the molecular sequelae and, in turn, treatment strategies for closed head injury.