Dietary reversal of cognitive impairment after traumatic brain injury

饮食逆转脑外伤后认知障碍

基本信息

批准号：
8292113
负责人：
Akiva S Cohen
金额：
$ 41.67万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292113
关键词：
Amino Acids Area Basic Science Brain Branched-Chain Amino Acids Caring Catabolism Cause of Death Child Clinic Clinical Cognitive Cognitive deficits Data Diet Dietary Intervention Direct Expenditure Drug Formulations Economics Equilibrium Future Glutamates Goals Healthcare Systems Hippocampus (Brain)Human Impaired cognition In Vitro Injury Intervention Learning Mediating Medical Memory Metabolic Metabolism Methodology Molecular Neurotransmitters Outcome Pathology Patients Physiological Protein Biosynthesis Public Health Research Services Structure Synapses Synaptic Transmission Testing Translating Traumatic Brain Injury United States Work cost dentate gyrus disability effective therapy gamma-Aminobutyric Acid hippocampal subregions in vivo mouse model neurotransmitter metabolism presynaptic public health relevance restoration young adult

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the primary cause of death and disability in young adults and children. It occurs every 21 seconds and afflicts up to two million people annually in the United States. TBI is a heterogeneous insult that precipitates a cascade of ripples that propagate severe long-lasting pathologies. The limbic hippocampus, a brain structure crucial for learning and memory is often damaged in TBI. It is still unknown how regional changes in cellular metabolism and neurotransmitter function contribute to cognitive impairment associated with TBI. However, our preliminary data suggest that post-traumatic regional shifts in hippocampal excitability are due in part to a change in metabolic priorities. Our key observation is that specific amino acids normally employed for neurotransmitter synthesis are potentially diverted to protein synthesis and catabolism for energy thus disturbing the necessary balance between excitation and inhibition. Significantly, dietary administration of branched chain amino acids (BCAAs) after injury results in comprehensive cognitive restoration. We have thus formulated the following CENTRAL HYPOTHESIS: Dietary intervention with branched chain amino acids restores posttraumatic cognitive deficit by ameliorating regional shifts in hippocampal excitability. To test this hypothesis, cellular metabolism, as well as excitatory and inhibitory function in hippocampal subregions will be studied from the molecular to the systemic level in a mouse model of TBI. Better understanding the temporal window and mechanism(s) contributing to our successful dietary intervention will enable the specific formulation of the most efficacious future intervention to alleviate this devastating (i.e. cognitive impairment) pathology. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major public health issue, which has a significant impact upon our healthcare system. Economic analyses of the annual cost of TBI-related disabilities range from $4.5 billion in direct expenditure (medical care and services) to $20.6 billion in injury-related work loss and disability. Our long-range goal is to continue to formulate an efficacious, safe and well- tolerated dietary intervention that can be rapidly translated from the bench to the clinic to ameliorate cognitive dysfunction in TBI patients.

描述（由申请人提供）：创伤性脑损伤（TBI）是年轻人和儿童死亡和残疾的主要原因。它每 21 秒发生一次，在美国每年影响多达 200 万人。 TBI 是一种异质性损伤，会引发一连串的连锁反应，传播严重的长期病变。边缘海马体是一种对学习和记忆至关重要的大脑结构，在创伤性脑损伤中经常受损。目前尚不清楚细胞代谢和神经递质功能的区域变化如何导致与 TBI 相关的认知障碍。然而，我们的初步数据表明，创伤后海马兴奋性的区域变化部分是由于代谢优先级的变化。我们的主要观察结果是，通常用于神经递质合成的特定氨基酸可能会转向蛋白质合成和分解代谢以获取能量，从而扰乱兴奋和抑制之间的必要平衡。值得注意的是，受伤后通过饮食摄入支链氨基酸（BCAA）可以实现全面的认知恢复。因此，我们提出了以下中心假设：支链氨基酸的饮食干预通过改善海马兴奋性的区域变化来恢复创伤后认知缺陷。为了检验这一假设，我们将在 TBI 小鼠模型中从分子水平到全身水平研究细胞代谢以及海马亚区的兴奋和抑制功能。更好地了解有助于我们成功饮食干预的时间窗口和机制，将使未来最有效的干预措施的具体制定成为可能，以减轻这种破坏性的（即认知障碍）病理。公共卫生相关性：创伤性脑损伤 (TBI) 是一个重大的公共卫生问题，对我们的医疗保健系统产生重大影响。对与 TBI 相关的残疾造成的年度成本的经济分析范围从 45 亿美元的直接支出（医疗保健和服务）到 206 亿美元的伤害相关工作损失和残疾。我们的长期目标是继续制定有效、安全且耐受性良好的饮食干预措施，该干预措施可以迅速从实验室转化为临床，以改善 TBI 患者的认知功能障碍。