Biomechanical Analysis of Traumatic Brain Injury Models

创伤性脑损伤模型的生物力学分析

基本信息

批准号：
6726025
负责人：
DAVID F MEANEY
金额：
$ 26.5万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-01 至 2006-04-30
项目状态：
已结题

项目摘要

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.

这是一个竞争性的延续应用程序，专注于创伤性脑损伤模型的生物力学分析。在上一个项目期间，我们确定了血管损伤和创伤性轴突损伤的机械阈值。这些原发性神经病理学变化虽然意义重大，但仅代表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体内细胞凋亡和坏死细胞死亡的局部机械应力条件，并测量不同脑区域对神经元和凋亡细胞死亡的机械耐受性的变化。我们的首要假设是细胞凋亡的机械阈值低于坏死细胞死亡阈值，并且皮层和海马体存在不同的机械阈值。我们进一步提出，机械拉伸导致细胞凋亡和坏死阈值水平引起的胞质钙立即变化的近端机制是不同的。研究的具体目标如下：（1）利用体内模型和有限元模拟测量体内神经元凋亡和坏死的机械阈值，（2）计算凋亡和坏死的相对体外机械阈值（3）确定两个大脑区域（皮质和海马）神经元的变化，以及（3）确定在坏死和凋亡的机械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，我们期望将描述受伤时发生的大脑区域变形的“机械应力图”转移到预测生物力学发生的细胞变化区域的“细胞反应图”。受伤时的力量。一旦完成，该研究将显着增强对现有模型的解释，以了解部分分子后遗症，进而了解闭合性颅脑损伤的治疗策略。