Biomechanical Analysis of Traumatic Brain Injury Models

这是一个竞争的延续应用程序，专注于创伤性脑损伤模型的生物力学分析。在最后一个项目期间，我们确定了血管损伤和创伤性轴索损伤的机械阈值。尽管意义重大，但这些初级神经病变只代表了创伤期间发生的事件的一小部分。在这个项目期间，我们的长期目标是确定区分活体内细胞凋亡性和坏死性细胞死亡的局部机械应力条件，并测量不同脑区对神经细胞和凋亡性细胞死亡机械耐受性的变化。我们的假设是，细胞凋亡的机械阈值低于坏死性细胞死亡阈值，大脑皮层和海马区存在不同的机械阈值。我们进一步提出，机械拉伸引起的细胞内钙在细胞凋亡和坏死阈值水平上的即刻移位的近端机制是不同的。本研究的具体目的如下：(1)利用体内模型和有限元模拟方法测量体内神经元凋亡和坏死的力学阈值；(2)计算大脑皮层和海马区神经元凋亡和坏死变化的相对体外力学阈值；(3)确定在坏死和凋亡的力学条件下导致神经元内钙内流的机制。通过实现研究计划的目标，我们希望将描述大脑在受伤时刻发生的局部变形的“机械应力图”转换为“细胞响应图”，该图预测在受伤期间生物机械力发生的细胞变化的区域。一旦完成，这项研究将大大加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.