TBI-Induced Cerebral Metabolic Depression and Recovery

这项建议的中心主题是确定创伤性脑损伤(TBI)后大脑葡萄糖的代谢目的地，从而发现接受干预(代谢治疗)的替代代谢途径，以促进细胞和功能恢复，并最终改变TBI患者管理的未来。两个基础科学项目将探索这些基本问题，旨在领导和补充两个临床项目。项目1(Richard Sutton博士)解决了在大鼠皮质受控撞击后给予葡萄糖和丙酮酸的问题，以检查它们对大脑代谢、细胞保护和结果的影响。项目2(Mayumi Prins博士)将使用燃料转运体的发育成熟作为自变量来研究出生后第35天和出生后90天的大鼠。燃料葡萄糖、乳酸和酮的转运体将根据它们的表达和功能进行测量。酮代谢的重点是这个项目的一个独特之处，因为它不仅解决了对结果的影响，而且还严格研究了适当的生化途径。项目3(Paul Vespa博士)主要从血糖浓度管理的角度探讨了人类脑损伤患者的葡萄糖底物供应问题。使用不同水平的胰岛素治疗，将对全球和局部大脑代谢的影响与细胞痛苦的神经化学和解剖学标记物进行比较。在创造性的交叉实验设计中，将为未来的临床试验收集初步数据。项目4(Neil Martin博士)将利用Kty-Schmidt技术解决人类受损大脑中葡萄糖的不同消耗。该计划中的研究人员将确定大脑葡萄糖消耗量的变化、转运体变化的影响、加强或限制葡萄糖输送的影响以及替代燃料的潜在使用。该计划项目将设在加州大学洛杉矶分校脑损伤研究中心(主任大卫·A·霍夫达博士)，以确保适当的成像、管理和实验室支持。

The central theme of this proposal is to identify the metabolic destination of cerebral glucose taken up after traumatic brain injury (TBI), thereby discovering alternative metabolic pathways receptive to interventions (metabolic therapy) to enhance cellular and functional recovery and ultimately change the future of TBI patient management. Two basic science projects will explore these fundamental issues, and are designed to lead as well as complement two clinical projects. Project 1 (Dr. Richard Sutton) addresses the administration of glucose and pyruvate following cortical controlled impact in the rat to examine their impact on cerebral metabolism, cellular protection and outcome. Project 2 (Dr. Mayumi Prins) will study postnatal day 35 and postnatal day 90 rats using the developmental maturation of fuel transporters as an independent variable. Transporters for the fuels glucose, lactate and ketones will be measured in terms of their expression and function. The focus of ketone metabolism is a unique feature in this project as it not only addresses the effect on outcome, but also rigorously studies the appropriate biochemical pathways. Project 3 (Dr. Paul Vespa) addresses the topic of glucose substrate supply for human TBI patients primarily from the perspective of management of serum glucose concentration. Using different levels of insulin therapy, the effect on global and regional cerebral metabolism will be compared to neurochemical and anatomical markers of cell distress. In a creative cross over experimental design preliminary data will be collected for a future clinical trail. Project 4 (Dr. Neil Martin) will utilize the Kety-Schmidt technique to address how glucose is consumed differently in the human injured brain. The investigators within this program will determine the change in the consumption of cerebral glucose, the effects of changes in transporters, and the effects of enhancing or restricting glucose delivery and the potential use of alternative fuels. This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support.