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。提出的研究导致了一个假设的测试，即与创伤性脑损伤（TBI）相关的年龄相关的变化可以通过增强神经元产生ATP的能力来消除。这个想法是基于这样一种理论，即脑线粒体中与年龄相关的变化导致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。年龄相关的线粒体氧化磷酸化缺陷会导致能量产生减少、细胞钙缓冲功能受损、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加速。我们实验室的初步数据显示实验性脑外伤后的年龄相关差异，支持其作为衰老动物模型的有效性。我们还提供了一些数据，表明补充肌酸的饮食对TBI有神经保护作用。由于缺乏足够的老年脑外伤动物模型的信息，本研究将首先描述与年龄相关的变化。具体目标#1将采用控制性皮质挫伤动物模型来描述脑外伤后形态学和行为变化的年龄相关下降。特异性目标#2将描述脑外伤后突触和非突触线粒体的年龄相关变化。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，这是继发性损伤的敏感标志物，以及TBI后脂质过氧化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“肌酸补充”饮食干预，增强细胞质磷酸肌酸，增加神经元产生ATP的能力，这是一种逆转年龄相关的TBI反应的干预。

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.