N-3 Fatty Acids and Outcomes in Pediatric Traumatic Brain Injury

N-3 脂肪酸和小儿创伤性脑损伤的结果

• 批准号: 7570325
• 负责人: BETH LEVANT
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-22 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570325
• 关键词: 4 year old; Abbreviations; Acute; Affect; Aftercare; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Behavioral; Biochemical; Blood - brain barrier anatomy; Brain; Cause of Death; Cessation of life; Child; Childhood; Clinical Research; Data; Diet; Docosahexaenoic Acids; Future; Goals; Inflammation; Injury; Intervention; Lead; Life; Maintenance; Matrix Metalloproteinases; Mediator of activation protein; Methods; Modeling; N-3 polyunsaturated fatty acid; Neuraxis; Neurobiology; Neurons; Nutritional; Omega-3 Fatty Acids; Outcome; Polyunsaturated Fatty Acids; Public Health; Rattus; Recovery; Research; Research Personnel; Risk; Role; Spinal cord injury; Stroke; Therapeutic Intervention; Tissues; Toddler; Traumatic Brain Injury; Variant; base; controlled cortical impact; disability; docosapentaenoic acid; feeding; high risk; improved; innovation; interdisciplinary approach; loss of function; motor deficit; neurochemistry; neuronal survival; novel; novel therapeutics; postnatal

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major public health concern with consequences including long-term loss of function or death. Accordingly, there is a significant need for improved treatments and other means for improving outcomes in TBI, especially in small children who are particularly likely to suffer such an injury. Mechanisms of TBI include inflammation, blood-brain barrier disruption, and neuronal death. The n-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) has anti- inflammatory and anti-apoptotic activities. Diet n-3 PUFA content influences the levels of DHA that are incorporated into tissues, including the brain, where DHA continues to accumulate into at least the second year of life. The American diet is notably low in n-3 PUFAs; thus, Americans are at particular risk of having low tissue DHA levels. Acute administration of DHA improves outcomes in animal models of spinal cord injury and stroke. However, it is not known whether DHA has beneficial effects in TBI or whether diet n-3 content, and thus tissue DHA levels, influence TBI outcomes. The PIs' overall goal is to improve outcomes of TBI in young children. The objective of this application is to determine the effects of diet n-3 PUFA content, acute DHA treatment, and their interaction on outcomes in a rat model of TBI in toddlers. The PIs hypothesize that low diet n-3 PUFA content will be associated with poorer TBI outcomes, that acute DHA treatment after TBI will improve outcomes, and that acute DHA treatment and diet n-3 PUFA content will interact to affect outcomes in TBI. An innovative approach, integrating nutritional and neurobiological methods will be used to pursue the following Specific Aims: 1) Determine the effects of diet n-3 PUFA content on outcomes of TBI and 2) Determine the effects of acute DHA administration on outcomes of TBI in rats fed diets varying in n-3 PUFA content. Disruption of the blood-brain barrier, which is central to the pathological sequelae after TBI, and functional motor deficits and recovery, will be assessed. Expected outcomes include readily translatable findings on the potential utility of DHA treatment and/or increased dietary n-3 PUFA content in improving outcomes in pediatric TBI, and greater understanding of the role of DHA in the central nervous system with respect to inflammation, maintenance of the blood-brain barrier, and neuronal survival/death. Such findings may be anticipated to form a basis for future clinical studies that lead to novel therapeutic and/or preventative interventions to improve outcomes in pediatric TBI. These data will also form a platform from which to launch expanded basic studies of mechanisms underlying the beneficial effects of DHA in TBI, which may be anticipated to lead to the identification of novel targets for therapeutic intervention in TBI. Relevance: Traumatic brain injury affects at least 1.4 million Americans each year and is a significant cause of death and long-term disability. Children 0-4 years old are at the highest risk. This study seeks to identify means to improve outcomes of TBI in young children.

描述（由申请人提供）：创伤性脑损伤（TBI）是一个主要的公共卫生问题，其后果包括长期功能丧失或死亡。因此，非常需要改进的治疗和其他手段来改善TBI的结果，特别是在特别可能遭受这种损伤的幼儿中。TBI的机制包括炎症、血脑屏障破坏和神经元死亡。n-3多不饱和脂肪酸（PUFA）二十二碳六烯酸（DHA）具有抗炎和抗凋亡活性。饮食中n-3 PUFA含量会影响DHA进入组织的水平，包括大脑，其中DHA至少在生命的第二年继续积累。美国人的饮食中n-3 PUFAs含量明显较低;因此，美国人的组织DHA水平特别低。DHA的急性给药改善了脊髓损伤和中风动物模型的结果。然而，目前尚不清楚DHA是否对TBI有有益作用，或者饮食中的n-3含量以及组织中的DHA水平是否会影响TBI的结果。PI的总体目标是改善幼儿TBI的结果。本申请的目的是确定饮食n-3 PUFA含量、急性DHA治疗及其相互作用对幼儿TBI大鼠模型结果的影响。PI假设低饮食n-3 PUFA含量将与TBI结果较差相关，TBI后的急性DHA治疗将改善结果，并且急性DHA治疗和饮食n-3 PUFA含量将相互作用以影响TBI的结果。一种创新的方法，整合营养和神经生物学方法将用于追求以下具体目标：1）确定饮食n-3 PUFA含量对TBI结果的影响，2）确定急性DHA给药对喂食n-3 PUFA含量不同饮食的大鼠TBI结果的影响。将评估血脑屏障的破坏，这是TBI后病理后遗症的核心，以及功能性运动缺陷和恢复。预期结果包括易于翻译的发现，DHA治疗和/或增加饮食n-3 PUFA含量在改善儿科TBI结果中的潜在效用，以及更好地理解DHA在中枢神经系统中炎症、血脑屏障维持和神经元存活/死亡方面的作用。这些发现可能会成为未来临床研究的基础，从而导致新的治疗和/或预防干预措施，以改善儿童TBI的结局。这些数据还将形成一个平台，从该平台启动DHA在TBI中的有益作用的基础机制的扩展基础研究，预计这可能导致识别TBI治疗干预的新靶点。 相关性：创伤性脑损伤每年影响至少140万美国人，是死亡和长期残疾的重要原因。0-4岁的儿童风险最高。本研究旨在确定改善幼儿TBI结果的方法。