Age-Dependent Ketone Metabolism After Brain Injury

脑损伤后年龄依赖性酮代谢

• 批准号: 6958787
• 负责人: Mayumi Lynn Prins
• 金额: $ 25.01万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6958787
• 关键词: age difference; autoradiography; behavior test; bioenergetics; brain injury; brain metabolism; glucose metabolism; growth factor receptors; immunocytochemistry; ketone body; laboratory rat; monoclonal antibody; neuroprotectants; nuclear magnetic resonance spectroscopy; receptor expression; trauma; vascular endothelial growth factors; western blottings

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.

描述（由申请人提供）：虽然在正常条件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条件下，向酮体的转变是代谢适应的常见形式。我们的实验室已经证明，酮可以有效地将幼年大鼠局灶性脑外伤 (TBI) 后的皮质挫伤体积减少 50%，但对成年大鼠则无效。酮的年龄依赖性神经保护作用使其与儿科 TBI 相关，而儿科 TBI 是美国 15 岁以下儿童死亡和残疾的第一大原因（Gotschall 等，1995）。该提议的中心假设是，脑酮代谢将改善 TBI 引起的脑能量危机，并以年龄依赖性方式减少细胞损失，并且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）通过组织学、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) 免疫组织化学和蛋白质印迹将用于确定年龄相关的神经保护差异是否是由于酮转运蛋白 (MCT) 的年龄依赖性上调所致 (3) 输注单克隆抗体以阻断血管内皮生长因子 (VEGF) 受体将用于确定 VEGF 是否是 MCT 上调的信号机制。 (4)离体1H-NMR和31P-NMR波谱将用于确定生酮神经保护的机制是否是改善脑生物能。 我们相信，使用酮体作为替代脑代谢底物可以在发育中的大脑中提供局灶性 TBI 后令人兴奋的治疗潜力，并为患有 TBI 的儿童提供急需的治疗选择。