Mechanisms of metabolic adaptation after traumatic brain injury

项目摘要/摘要 创伤性脑损伤(TBI)会导致终身认知和运动障碍。颅脑损伤引起急性和 长时间的代谢适应，试图提供生理燃料并使生存 受损的神经组织。这项提案的总体目标是确定 对损伤的代谢适应和促进脑损伤后恢复的代谢要求。 颅脑损伤的病理生理机制是复杂的，主要特征是血糖调节失调。 新陈代谢。然而，大脑含有高浓度的脂肪酸，这些脂肪酸是从 颅脑损伤后的质膜和通过促进炎症进一步传播继发性损伤 和脂质过氧化。我们已经证明，大脑能够利用这些脂肪酸提供能量 并通过β氧化代谢。具体地说，这种机制存在于神经前体细胞和 星形胶质细胞。因此，这一机制允许将脂肪酸重新定向到线粒体进行β氧化。 重要的是，我们的初步数据显示，脑创伤后脂肪酸氧化增加。 受伤。我们假设受伤的大脑需要上调脂肪酸氧化。 特别是在星形胶质细胞中，以便为神经元节省葡萄糖，并消除有毒脂肪酸 神经组织和血脑屏障受损后的中间体。使用特定于组织的 转基因和基因敲除小鼠模型，我们将测试这一假设，并详细说明这些基本原理 悬而未决的问题。为了检验这些假设，我们提出了三个具体目标：1)确定 脑创伤后脑内脂肪酸代谢的时空贡献；2)确定 脑创伤后对脑脂肪酸氧化的要求；3)确定全身性 脑外伤后的代谢适应。这个项目的长期目标是确定监管 以及对创伤后脂肪酸氧化途径的要求。因此，这些研究将阐明 脂肪酸代谢在损伤后被调节，并促进了我们对代谢的理解 改编。此外，基础知识是如何改变脂肪酸代谢的脑损伤后 可能导致有针对性的治疗，以改善神经侮辱后的大脑能量和新陈代谢。 好了！

PROJECT SUMMARY / ABSTRACT Traumatic brain injury (TBI) results in life-long cognitive and motor disabilities. TBI elicits acute and prolonged metabolic adaptations in an attempt to provide physiological fuel and to enable the survival of damaged nervous tissue. The overall objective of this proposal is to determine the mechanisms of metabolic adaptation to injury and the metabolic requirements that promote recovery following TBI. The pathophysiology of TBI is complex and characterized largely by dysregulated glucose metabolism. However, brain contains high concentration of fatty acids, which are liberated from plasma membrane following TBI and further propagate secondary injury by promoting inflammation and lipid peroxidation. We have shown that brain is capable of utilizing these fatty acids for energy and metabolism via β-oxidation. Specifically, this mechanism is present in neural progenitor cells and astrocytes. Thus, this mechanism allows to re-direct fatty acids to mitochondria for β-oxidation. Importantly, our preliminary data show that fatty acid oxidation is increased following traumatic brain injury. We hypothesize that the injured brain requires the up-regulation of fatty acid oxidation specifically in astrocytes in order to spare glucose for neurons as well as eliminating toxic fatty acid intermediates following damage to nervous tissue and blood brain barrier. Using tissue specific transgenic and knockout mouse models, we will test this hypothesis and detail these fundamental unanswered questions. To test these hypothesis we propose three specific aims: 1) Determine the spatial and temporal contribution of brain fatty acid metabolism following TBI; 2) Determine the requirement for brain fatty acid oxidation following TBI; 3) Determine the requirements for systemic metabolic adaptations following TBI. The long-term goal of this project is to determine the regulation and requirement for fatty acid oxidation pathway following TBI. Thus, these studies will elucidate how fatty acid metabolism is regulated following the injury and advance our understanding of metabolic adaptations. Furthermore, the fundamental knowledge how fatty acid metabolism is altered after TBI could lead to targeted therapies to improve brain energy and metabolism after neurological insult. !