NEUROMETABOLIC PATHOBIOLOGY OF TRAUMATIC BRAIN INJURY

加州大学洛杉矶分校脑损伤研究计划的总体目标是 了解人类创伤性脑损伤（TBI）的神经生物学。我们 基础科学的努力已经描述了许多神经化学和 TBI引发的代谢级联反应通过这些努力，我们 描述了TBI如何增加细胞外钾浓度。 这种损伤引起的离子流增加了驱动能量的需求 钠/钾泵对这种能源的需求主要是满足 糖酵解的选择性激活。利用[14 C]脱氧-D- 葡萄糖放射自显影在实验动物，我们已经能够 检测这种损伤诱导的糖酵解过度的程度，从而获得 一个“侮辱的形象。" 结合传统和最先进的代谢成像 研究，我们已经成功地记录了损伤引起的 在人TBI之后发生糖酵解过度。从我们的初步调查结果来看， 葡萄糖代谢增加背后的机制及其对 神经生理学与我们在动物身上所描述的完全相同 TBI模型目前的建议利用了这一意见， 设计两个临床和一个基础科学项目，每个项目都涉及 这一前所未有的发现的不同但相互关联的方面。一 项目将确定总体糖酵解亢进的发生率 在TBI之后利用动脉-静脉差异。一个项目将 确定人TBI后糖酵解亢进的区域分布 利用正电子发射断层扫描。这两个项目将解决 意识形态和后果的高糖酵解后TBI与特定 重点关注神经化学、脑血流量和乳酸的变化 生产一个项目将确定高糖酵解的影响， 细胞对二次损伤的脆弱性。实验 该项目的设计将解决大脑的程度和范围 TBI后血流-代谢解偶联及其与细胞凋亡的关系 生存 我们的一般假设是，糖酵解过度，定义为 葡萄糖和氧化代谢之间的代谢比例，是一个不变的 TBI的后果糖酵解过度是细胞能量需求的结果 直接响应离子流。燃料需求的增加导致 在代谢危机期间，脑血流可能无法 这反映了能源生产效率低下， 乳酸的积累。这种代谢危机定义了 伤害的程度，并提供了重要的见解，以解释为什么 脑外伤后大脑会变得很脆弱

The overall goal of the UCLA Brain Injury Research Program is to understand the neurobiology of human traumatic brain injury (TBI). Our basic science efforts have described much of the neurochemical and metabolic cascade that is initiated by TBI. Out of these efforts, we have described how TBI increases the extracellular concentration of potassium. This injury-induced ionic flux increased the demand for energy to drive sodium/potassium pumps. The demand for this energy is primarily satisfied from the selective activation of glycolysis. Utilizing [/14C]deoxy-D- glucose autoradiography in experimental animals, we have been able to detect the extent of this injury-induced hyperglycolysis thereby obtaining an "image of the insult." Incorporation both conventional and state-of-the-art metabolic imaging studies, we have been successful in documenting that the injury-induced hyperglycolysis occurs following human TBI. From our preliminary findings, the mechanisms behind the increase in glucose metabolism and its effect on neurophysiology are identical to what we have described in our animal models of TBI. The current proposal takes advantage of this observation by designing two clinical and one basic science projects, each addressing different, but interrelated, aspects of this unprecedented finding. A Project will determine the incident rate of global hyperglycolysis following TBI utilizing arterial-venous differences. A Project will determine the regional distribution of hyperglycolysis following human TBI utilizing positron emission tomography. Both projects will address the ideology and consequences of hyperglycolysis following TBI with specific emphasis on the changes in neurochemistry, cerebral blood flow and lactate production. A Project will determine the implication of hyperglycolysis in terms of cellular vulnerability to secondary insults. The experimental design of this project will address the degree and extent of cerebral blood flow-metabolic uncoupling following TBI and how this relates to cell survival. Our general hypothesis is that hyperglycolysis, defined in terms of the metabolic ratio between glucose and oxidative metabolism, is a immutable consequence of TBI. Hyperglycolysis is a result of cellular energy demands in direct response to ionic fluxes. This increase in fuel demand results in a metabolic crisis during which cerebral blood flow may not be sufficient and reflects an inefficient production of energy, resulting in the accumulation of lactate. This metabolic crisis define the degree and extent of injury and provides important insight into explaining why the brain in so vulnerable following TBI.