RESPONSE OF THE AGING NERVOUS SYSTEM TO TRAUMA

描述(由申请人提供)：大量的临床数据表明，老化的神经系统受到创伤后，发病率和死亡率会增加。目前对这种放大的不良反应背后的细胞底物知之甚少。拟议的研究导致了对这一假设的检验，即与创伤性脑损伤(TBI)相关的年龄相关变化可以通过增强神经元产生ATP的能力来否定。这个想法是基于这样一种理论，即大脑线粒体的年龄相关变化会导致满足创伤后神经元能量需求所必需的ATP中断。线粒体是神经功能所需的三磷酸腺苷的主要来源。与年龄相关的线粒体氧化磷酸化缺陷导致能量产生减少，细胞钙缓冲受损，蛋白水解酶和磷脂酶激活，自由基产生增加。所有这些途径都可能导致增强的细胞死亡，这取决于侮辱的严重程度。我们实验室的初步数据显示，实验性脑外伤后与年龄相关的差异，支持其作为衰老动物模型的有效性。我们还提供了补充肌酸的饮食为脑外伤提供神经保护干预的数据。由于缺乏关于脑外伤老龄动物模型的足够信息，本研究将首先描述与年龄相关的变化。具体目标#1将利用受控皮质挫伤的动物模型来表征脑外伤后与年龄相关的形态和行为变化的下降。具体目标#2将描述脑外伤后突触和非突触线粒体与年龄相关的变化。具体目标#3将探索与年龄相关的乳酸和游离脂肪酸生成的变化，这些是继发性损伤的敏感标志物，以及脑外伤后脂质过氧化的标志物异前列腺素和神经前列腺素的变化。具体目标#4将使用“补充肌酸”的饮食干预措施，提高细胞内磷酸肌酸水平，提高神经元产生三磷酸腺苷的能力，这是一种逆转与年龄有关的脑损伤反应的干预措施。

DESCRIPTION (provided by applicant): Abundant clinical data indicate increased morbidity and mortality following trauma to the aging nervous system. Little is currently known about the cellular substrates underlying this amplified adverse response. The proposed studies lead to testing of the hypothesis, that age-related changes associated with traumatic brain injury (TBI) can be negated by enhancing the ability of neurons to produce ATP. This idea is based on the theory that age-related changes in brain mitochondria lead to a disruption of ATP necessary to meet the energy demands of neurons following trauma. Mitochondria are the major source of ATP required for neuronal function. Age-related defects in mitochondrial oxidative phosphorylation result in deceased energy production, impaired cellular calcium buffering, activation of proteases and phospholipases, and the generation of increased free radicals. All of these pathways can lead to enhanced cell death depending on the severity of the insult. Preliminary data from our laboratory demonstrate age-related differences following experimental TBI, supporting its usefulness as an aging animal model. We also present data that a diet supplemented by creatine provides a neuroprotective intervention for TBI. Because of a lack of sufficient information on aged animal models of TBI, this study will first characterize age-related changes. Specific aim #1 will characterize age-related decline in morphologic and behavioral changes following TBI employing an animal model of controlled cortical contusion. Specific aim #2 will characterize age-related changes in synaptic and non-synaptic mitochondria following TBI. Specific aim #3 will explore age-related changes in the generation of lactic acid and free fatty acids, sensitive markers of secondary injury, and changes in isoprostanes and neuroprostanes, markers of lipid peroxidation following TBI. Specific aim #4 will use a 'creatine-supplemented' dietary intervention that enhances cytosolic phosphocreatine and increases the ability of neurons to produce ATP, an intervention to reverse the age-related response to TBI.