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）：虽然葡萄糖仍然是正常条件下的主要脑代谢底物，但在能量需求增加或葡萄糖可用性降低的条件下，转移到酮体是代谢适应性的一种常见形式。我们的实验室已显示酮在少年大鼠（而不是成年大鼠）中有效减少50％的皮质挫伤量增加了50％。酮的年龄依赖性神经保护使其与小儿TBI有关，这是美国15岁以下儿童死亡和残疾的第一名（Gotschall等，1995）。该提议的核心假设是，脑酮代谢将改善TBI诱导的大脑能量危机并以年龄依赖性的方式减少细胞损失，并且酮的大脑转运的成熟差异会导致这种年龄效应。以下提案针对4个特定目的：（1）组织，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）免疫组织化学和西方人将用于确定神经保护剂与年龄相关的差异是否是由于年龄依赖性的酮转运蛋白（MCT）（3）单克隆抗体的上调以阻断血管内皮生长因子（VEGGF）受体的单克隆抗体（VEVGF）的usctrage insctregregry机构是否有机构。 （4）将使用EX-VIVO 1H-NMR和31P-NMR光谱法来确定生酮神经保护的机理是否改善了脑生物能力。 我们认为，在发育中的大脑中，使用酮体作为替代性脑代谢底物具有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。