RESPONSE OF THE AGING NERVOUS SYSTEM TO TRAUMA

描述（由申请人提供）：大量临床数据表明衰老神经系统创伤后发病率和死亡率增加。目前对这种放大的不良反应背后的细胞底物知之甚少。拟议的研究对这一假设进行了检验，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 的能力来消除。这一想法基于这样的理论：大脑线粒体中与年龄相关的变化会导致 ATP 的破坏，而 ATP 是满足创伤后神经元能量需求所必需的。线粒体是神经元功能所需 ATP 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、蛋白酶和磷脂酶激活以及自由基产生增加。根据损伤的严重程度，所有这些途径都可能导致细胞死亡增加。我们实验室的初步数据表明，实验性 TBI 后存在与年龄相关的差异，支持其作为衰老动物模型的有用性。我们还提供的数据表明，补充肌酸的饮食可为 TBI 提供神经保护干预。由于缺乏关于老年 TBI 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将采用受控皮质挫伤的动物模型来描述TBI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 TBI 后突触和非突触线粒体与年龄相关的变化。具体目标#3将探讨乳酸和游离脂肪酸生成的年龄相关变化（继发性损伤的敏感标志物），以及异前列腺素和神经前列腺素（TBI后脂质过氧化标志物）的变化。具体目标#4 将使用“补充肌酸”的饮食干预措施，增强胞浆磷酸肌酸并提高神经元产生 ATP 的能力，这是一种逆转与年龄相关的 TBI 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.