Age-Dependent Ketone Metabolism After Brain Injury

描述（由申请方提供）：虽然葡萄糖在正常条件下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条件下，向酮体转移是一种常见的代谢适应形式。我们的实验室已经表明，酮可有效减少幼年大鼠局灶性创伤性脑损伤（TBI）后50%的皮质挫伤体积，但对成年大鼠无效。酮的年龄依赖性神经保护作用使其与儿科TBI相关，这是美国15岁以下儿童死亡和残疾的首要原因（Gotschall et al. 1995）。该建议的中心假设是，脑酮代谢将改善TBI诱导的脑能量危机，并以年龄依赖性方式减少细胞丢失，脑酮转运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）组织学、功能和行为分析将用于确定不同年龄损伤后生酮治疗的有效性。(2)将使用免疫组织化学和western来确定神经保护的年龄相关差异是否是由于酮转运蛋白（MCT）的年龄依赖性上调所致（3）将使用单克隆抗体输注来阻断血管内皮生长因子（VEGF）受体来确定VEGF是否是MCT上调的信号传导机制。(4)将使用离体1H-NMR和31 P-NMR光谱来确定生酮神经保护的机制是否是改善的脑生物能量学。 我们认为，使用酮体作为替代脑代谢底物，在发育中的大脑中局灶性TBI后提供了令人兴奋的治疗潜力，并为TBI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.