TBI-Induced Cerebral Metabolic Depression and Recovery

本提案的中心主题是确定创伤性脑损伤（TBI）后脑葡萄糖的代谢目的地，从而发现可接受干预（代谢治疗）的替代代谢途径，以增强细胞和功能恢复，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，并旨在引导和补充两个临床项目。项目1 （Dr. Richard Sutton）研究了葡萄糖和丙酮酸在大鼠大脑皮层控制作用下的管理，以检查它们对脑代谢、细胞保护和结果的影响。项目2 （Mayumi Prins博士）将以燃料转运体的发育成熟为自变量，研究出生后35天和出生后90天的大鼠。葡萄糖、乳酸和酮类燃料的转运体将根据其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，而且严格研究了适当的生化途径。项目3 （Paul Vespa博士）主要从管理血清葡萄糖浓度的角度探讨了人类TBI患者葡萄糖底物供应的主题。使用不同水平的胰岛素治疗，对整体和区域脑代谢的影响将与细胞窘迫的神经化学和解剖学标志物进行比较。在一个创造性的交叉实验设计中，将为将来的临床试验收集初步数据。项目4（尼尔·马丁博士）将利用凯蒂-施密特技术来解决葡萄糖在人类受伤的大脑中消耗的不同。该项目的研究人员将确定脑葡萄糖消耗的变化，转运体变化的影响，增强或限制葡萄糖输送的影响以及替代燃料的潜在使用。该项目将被安置在加州大学洛杉矶分校脑损伤研究中心（Dr. David A. Hovda，主任），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.