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 急性和急性期脑葡萄糖代谢（ICMRgl）和血流量（ICBF） 皮质液冲击损伤（FPI）后的亚急性期 鼠。使用新颖的 3D 放射自显影图像获得令人兴奋的试验数据 - 我们开发的平均策略揭示了显着的新陈代谢 > FPI 后急性期的流动解耦，我们认为这会强加 对组织造成严重的代谢压力。相比之下，充血 观察五天。使用匹配的动物组和差异 分析算法，综合表征ICBF、ICMRgl 以及 FPI 后前五天内的 ICMRgl/ICBF 比率。我们 假设解耦在最初的几个小时内持续存在，但是 1-2天后缓解。接下来，我们将确定这些扰动如何 受到创伤后治疗性低温的影响， 要么早（前 3 小时）。或稍后开始（3-5小时） 创伤。我们假设治疗性低温可逆转解偶联 从而保护组织。我们将确立以下角色： 创伤后 ICBF 中的一氧化氮/一氧化氮合酶 (NOS) 系统 变化，要么通过急剧减少血管NO产生，要么通过 稍后iNOS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， 结合外伤脑中循环 GMP 产生的评估。 由于内皮素和/或血清素是 ICBF 的潜在调节剂，因此 创伤，这些也将通过脑内微透析进行评估 使用特定的药理学拮抗剂。最后，我们打算 更全面地描述本地证据之间的关系 代谢应激（代谢>解偶联）和时间和 基因表达的空间特征：我们将重点关注hsp7O， 立即早期基因、胶质纤维酸性蛋白和 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，揭示了与创伤相关的基因表达变化。这 这些基因表达模式与细胞凋亡的关系将是 评估。最后我们要考察一下具体的效果 治疗干预，包括 NMDA 和非 NMDA 拮抗，以及 氧自由基的清除、CMRgl/CBF 相互关系和 基因表达。这些研究将提供全面的概述 急性期和亚急性期的血流动力学和代谢。