Age-Dependent Ketone Metabolism After Brain Injury

描述(申请人提供)：虽然葡萄糖在正常情况下仍然是大脑的主要代谢底物，但在能量需求增加或葡萄糖供应减少的情况下，转移到酮体是一种常见的代谢适应形式。我们的实验室已经证明，酮可以有效地减少幼年大鼠局灶性脑损伤(TBI)后皮质挫伤体积的50%，但成年大鼠不能。酮的年龄依赖性神经保护使其与儿童脑外伤有关，脑损伤是美国15岁以下儿童死亡和残疾的头号原因(Gotschall等人。1995年)。该方案的中心假设是，脑酮代谢将改善脑损伤所致的脑能量危机，并以一种年龄依赖的方式减少细胞损失，而脑酮转运的成熟差异是这种年龄效应的原因。以下建议针对4个具体目标：(1)组织学、功能和行为分析将被用来确定不同年龄段损伤后生酮治疗的效果。(2)免疫组织化学和免疫印迹法将被用来确定与年龄相关的神经保护差异是否是由于酮转运体(MCT)的年龄依赖性上调所致。(3)应用阻断血管内皮生长因子(VEGF)受体的单抗将被用来确定VEGF是否是MCT上调的信号机制。(4)体外1H-核磁共振和31P-核磁共振波谱将用于确定生酮神经保护的机制是否为改善脑生物能量学。 我们相信，使用酮体作为替代的大脑代谢底物，在发育中的大脑中的局灶性脑损伤后提供了令人兴奋的治疗潜力，并为脑损伤儿童提供了迫切需要的治疗选择。

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.