ACUTE/SUBACUTE METABOLIC & HEMODYNAMIC TRAUMATIC BRAIN INJURY DETERMINANTS

急性/亚急性代谢

• 批准号: 6455813
• 负责人: MYRON DAVID GINSBERG
• 金额: $ 23.88万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6455813
• 关键词: NMDA receptors; brain circulation; brain injury; brain metabolism; disease /disorder model; endothelin; free radical oxygen; free radical scavengers; glial fibrillary acidic protein; glucose metabolism; immunocytochemistry; in situ hybridization; induced hypothermia; laboratory rat; microdialysis; nitric oxide; regulatory gene; trauma

We propose to investigate in detail the interrelationships between local brain glucose metabolism (ICMRgl) and blood flow (ICBF) in the acute and subacute periods following cortical fluid-percussion injury (FPI) in the rat. Exciting pilot data obtained using novel 3D autoradiographic image- averaging strategies developed by us have disclosed marked metabolism > flow uncoupling in the acute period after FPI, which we believe imposes a severe metabolic stress upon the tissue. In contrast, hyperemia was observed at five days. Using matched animal groups and the disparity analysis algorithm, we shall comprehensively characterize ICBF, ICMRgl and the ICMRgl/ICBF ratio over the first five days following FPI. We hypothesize that uncoupling persists during the first few hours but remits after 1-2 days. Next, we shall ascertain how these perturbations are influenced by post-traumatic therapeutic hypothermia, administered either early (first 3 h). or initiated somewhat later (3-5 h) following trauma. We hypothesize that therapeutic hypothermia reverse uncoupling and thereby protects the tissue. We shall establish the role of the nitric oxide/nitric oxide synthase (NOS) system in post-traumatic ICBF changes, either via diminished vascular NO production acutely or by expression of iNOS at later time. This will be studied via in situ hybridization, immunohistochemistry, and enzymatic activity assays, coupled with assessment of cyclic GMP production in the traumatic brain. As endothelin and/or serotonin are potential modulators of ICBF following trauma, these will also be assessed via intracerebral microdialysis and the use of specific pharmacologic anatagonists. Finally, we intend to characterize more fully the relationship between the localized evidence of metabolic stress (metabolism > uncoupling) and the temporal and spatial features of gene expression: we shall concentrate on hsp7O, immediate early genes, glial fibrillary acidic protein, and the neurotrophin, brain- derived neurotrophic factor. Our pilot data, in each instance, have revealed trauma-related changes in gene expression. The relationship of these patterns of gene expression to apoptosis will be assessed. Finally, we shall investigate the effect of specific therapeutic interventions, including NMDA and non-NMDA antagonism, and the scavenging of oxygen radicals, on CMRgl/CBF interrelationships and gene expression. These studies will provide a comprehensive overview of hemodynamics and metabolism in the acute and subacute periods.

我们建议详细研究本地之间的相互关系 急性中的脑葡萄糖代谢（ICMRGL）和血流（ICBF） 皮质流体渗透损伤（FPI）的亚急性期 鼠。使用新颖的3D自显影图像获得的令人兴奋的飞行员数据 - 我们制定的平均策略已揭示了明显的新陈代谢> 在FPI之后的急性时期，流动解偶，我们认为这会施加 组织上的代谢应激。相反，充血是 观察到五天。使用匹配的动物群体和差异 分析算法，我们将全面地表征ICBF，ICMRGL 以及FPI之后的前五天，ICMRGL/ICBF比率。我们 假设在最初的几个小时内，解偶联仍然存在 1-2天后汇款。接下来，我们将确定这些扰动如何 受创伤后治疗性体温过低的影响 早期（前3小时）。或以后启动（3-5 h）以下 创伤。我们假设治疗性体温过低反偶联 从而保护组织。我们将确定 创伤后ICBF中的一氧化氮/一氧化氮合酶（NOS）系统 变化，要么通过急性生产的血管降低或通过 以后的iNOS表达。这将通过原位研究 杂交，免疫组织化学和酶活性测定， 再加上创伤性大脑中环状GMP产生的评估。 因为内皮素和/或5-羟色胺是ICBF的潜在调节剂 创伤，这些也将通过脑内微透析和 使用特定的药理学分室家。最后，我们打算 更充分地表征本地证据之间的关系 代谢压力（代谢>解偶联）和时间和时间 基因表达的空间特征：我们将集中于Hsp7o， 直接的早期基因，神经胶质原纤维酸性蛋白和 神经营养蛋白，脑衍生的神经营养因子。我们的飞行员数据，每个数据 实例，已经揭示了基因表达与创伤相关的变化。这 这些基因表达模式与凋亡的关系将是 评估。最后，我们将研究特定的效果 治疗干预措施，包括NMDA和非NMDA拮抗作用，以及 在CMRGL/CBF相互关系上清除氧自由基和 基因表达。这些研究将提供全面的概述 在急性和亚急性期间的血液动力学和代谢。