Age-Dependent Ketone Metabolism After Brain Injury

描述（由申请人提供）：在正常情况下，葡萄糖仍然是主要的脑代谢底物，但在能量需求增加或葡萄糖可用性降低的情况下，向酮体转移是一种常见的代谢适应形式。我们的实验室已经证明，在幼年大鼠中，酮类可以有效地减少局灶性创伤性脑损伤（TBI）后50%的皮质挫伤体积，而不是成年大鼠。酮类具有年龄依赖性的神经保护作用，这与儿童脑外伤有关，而儿童脑外伤是美国15岁以下儿童死亡和残疾的头号原因（Gotschall et al. 1995）。该建议的中心假设是脑酮代谢将以年龄依赖的方式改善tbi诱导的脑能危机和减少细胞损失，并且脑酮运输的成熟差异解释了这种年龄效应。以下建议针对4个具体目标：(1)将使用组织学，功能和行为分析来确定不同年龄损伤后生酮治疗的有效性。(2)免疫组织化学和western将用于确定年龄相关的神经保护差异是否由于酮转运体（MCT）的年龄依赖性上调所致。(3)通过输注单克隆抗体阻断血管内皮生长因子（VEGF）受体来确定VEGF是否是MCT上调的信号机制。(4)利用离体1H-NMR和31P-NMR波谱来确定生酮神经保护的机制是否通过改善大脑生物能量学来实现。

DESCRIPTION (provided by applicant): While glucose remains the primary cerebral metabolic substrate under normal conditions, shifting to ketone bodies is a common form of metabolic adaptation demonstrated under conditions of increased energy demands or decreased glucose availability. Our laboratory has shown ketones to be effective in reducing cortical contusion volume by 50% following focal traumatic brain injury (TBI) among juvenile, but not adult rats. The age-dependent neuroprotection of ketones makes it relevant to pediatric TBI, which is the #1 cause of death and disability among children under 15 years of age in the US (Gotschall et al. 1995). The central hypothesis of this proposal is that cerebral ketone metabolism will improve TBI-induced cerebral energy crisis and reduce cell loss in an age-dependent manner and that maturational differences in cerebral transport of ketones accounts for this age effect. The following proposal is directed at 4 specific aims: (1) Histological, functional and behavioral analysis will be used to determine the effectiveness of ketogenic therapy after injury in different ages. (2) Immunohistochemistry and westerns will be used to determine the whether age-related differences in neuroprotection are due to age-dependent upregulation of ketone transporters (MCT) (3) Infusion of monoclonal antibodies to block the vascular endothelial growth factor (VEGF) receptor will be used to determine whether VEGF is the signaling mechanisms for MCT upregulation. (4) Ex-vivo 1H-NMR and 31P-NMR spectroscopy will be used to determine whether the mechanism of ketogenic neuroprotection is improved cerebral bioenergetics. We believe that the use of ketone bodies as an alternative cerebral metabolic substrate offers exciting therapeutic potential following focal TBI in the developing brain and offers desperately needed treatment options for children with TBI.