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.

我们建议详细调查地方之间的相互关系 脑葡萄糖代谢（ICMRgl）和血流量（ICBF）在急性和 皮质液体撞击损伤（FPI）后的亚急性期 大鼠使用新型3D放射自显影图像获得的激动人心的飞行员数据- 我们开发的平均策略揭示了显著的新陈代谢> FPI后急性期的血流解偶联，我们认为 对组织造成严重的代谢压力相反，充血是 观察了五天。使用匹配的动物组和差异 分析算法，我们将全面表征ICBF，ICMRgl 以及FPI后前五天内的ICMRg 1/ICBF比率。我们 假设在最初的几个小时内解偶联持续， 1-2天后汇款。接下来，我们将确定这些扰动如何 受到创伤后低温治疗的影响， 早期（前3小时）。或稍晚（3-5小时）开始， 外伤我们假设治疗性低温可以逆转解偶联 从而保护组织。我们将确立 一氧化氮/一氧化氮合酶系统在创伤后ICBF中的作用 变化，无论是通过减少血管NO生产急性或 诱导型一氧化氮合酶的表达。这将通过现场研究 杂交、免疫组织化学和酶活性测定， 再加上创伤性脑中环GMP产生的评估。 由于内皮素和/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进行评估， 使用特定的药理学抗激动剂。最后，我们打算 更充分地描述本地化证据之间的关系， 代谢应激（代谢>解偶联）和时间和 基因表达的空间特征：我们将集中于hsp 70， 即早基因，胶质细胞酸性蛋白， 神经营养因子，脑源性神经营养因子。我们的试点数据，在每个 例如，已经揭示了基因表达中与创伤相关的变化。的 这些基因表达模式与细胞凋亡的关系将是 评估。最后，我们将研究特定的 治疗干预，包括NMDA和非NMDA拮抗作用，以及 清除氧自由基，CMRgl/CBF相互关系， 基因表达。这些研究将全面概述 急性期和亚急性期的血流动力学和代谢。