NEUROMETABOLIC PATHOBIOLOGY OF TRAUMATIC BRAIN INJURY

加州大学洛杉矶分校脑损伤研究项目的总体目标是 了解人类创伤性脑损伤(TBI)的神经生物学。我们的 基础科学的工作已经描述了许多神经化学和 由脑损伤引发的代谢级联反应。在这些努力中，我们有 描述了TBI如何增加细胞外钾的浓度。 这种由伤害引起的离子通量增加了驾驶所需的能量 钠/钾泵。对这种能源的需求基本上得到了满足。 来自糖酵解的选择性激活。利用[/14C]脱氧-D- 在实验动物中进行葡萄糖放射自显影，我们已经能够 检测这种损伤引起的高糖酵解的程度，从而获得 一种“侮辱的形象”。 融合了传统和最新的代谢成像技术 研究表明，我们已经成功地记录了 人脑外伤后会发生高糖酵解。从我们的初步调查结果来看， 糖代谢增加背后的机制及其对糖尿病的影响 神经生理学与我们在动物身上所描述的完全相同。 TBI的模型。目前的提案通过以下方式利用了这一观察结果 设计两个临床项目和一个基础科学项目，每个项目都针对 这一史无前例的发现有不同但又相互关联的方面。一个 项目将确定全球高糖酵解的发生率 脑外伤后利用动-静脉差异。一个项目将 确定人脑外伤后高糖酵解的区域分布 利用正电子发射断层扫描。这两个项目都将解决 特发性脑损伤后高糖酵解的思想和后果 重视神经化学、脑血流量和乳酸的变化 制作。一个项目将确定高糖酵解的含义 细胞对二次侮辱的脆弱性。实验性的 本项目的设计将解决脑损伤的程度和程度 颅脑损伤后血流-代谢解偶联及其与细胞的关系 生死存亡。 我们的一般假设是高糖酵解，定义为 葡萄糖和氧化代谢之间的代谢比例，是一成不变的 颅脑损伤的后果。高糖酵解是细胞能量需求的结果 对离子通量的直接反应。这种燃料需求的增加导致了 在代谢危机期间，大脑血流可能不会 并反映了能源生产的低效，导致 乳酸的积累。这种新陈代谢危机定义了 并提供了重要的洞察力来解释为什么 脑损伤后脑部如此脆弱。

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.