酮体代谢对急性脊髓损伤神经保护作用机制的研究

项目名称： 酮体代谢对急性脊髓损伤神经保护作用机制的研究

项目编号： No.81472084

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 朱青安

作者单位： 南方医科大学

项目金额： 61万元

中文摘要： 生酮饮食或隔日禁食均使机体出现酮体代谢，提高β羟丁酸水平。我们前期研究证实大鼠急性脊髓损伤（SCI）后给予生酮饮食或隔日禁食都有明显的神经保护作用。近来发现β羟丁酸是组蛋白去乙酰化酶（HDACs）的内源性抑制剂，在肾脏组织中调节抗氧化应激因子的基因水平。我们继而发现酮体代谢导致正常脊髓组织的乙酰化水平上升和基因上调，为阐明其对SCI的神经保护机制提供了依据。由此，我们提出新理论假设：β羟丁酸特异性阻滞损伤脊髓的HDACs，抑制急性SCI的氧化应激；抗氧化应激因子的基因转录水平的调节和氧化应激的抑制程度与β羟丁酸有剂量相关性。本项目研究：1)酮体代谢对大鼠颈脊髓挫伤后脊髓HDACs的抑制和抗氧化应激因子的基因转录水平调节；2)阻断酮体转运的影响；3)酮体代谢治疗SCI远期的脊髓组织乙酰化和氧化应激程度；4）隔日生酮饮食对急性SCI的神经保护作用。这将为SCI治疗提出新理论，发展新的干预途径。

中文关键词： 酮体代谢；脊髓损伤；神经保护；组蛋白去乙酰化酶；β羟丁酸

英文摘要： Ketogenic diet (KD) with high fat and low carbohydrate, and calorie restriction in the form of every-other-day fasting (EODF) result in ketone body metabolism and increase the β-hydroxybutyrate (βOHB) level. We discovered that KD or EODF improved outcomes after an incomplete cervical spinal cord contusion injury. Exciting new data show that βOHB is an endogenous histone deacetylase inhibitor, resulting in an incrase of gene expression of oxidative stress resistance in kidney. We recently found that ketone body metabolisms enhanced acetylation and regulated gene expression in normal spinal cord, paving the way for neuroprotective mechanism of acute spinal cord injury under ketone body metabolism. Our overall hypothesis is that βOHB induced by ketone body metabolisms is an endogenous and specific inhibitor of histone deacetylase, increases histon acetylation in the spinal cord tissue and suppresses the oxidative stress after SCI. Changes in transcription of the genes encoding oxidative stress factors, and SCI oxidative stress is dose-dependent to the βOHB level. This study aims to: 1) explore effects of βOHB induced by ketone body metabolisms on expression of genes related to suppression of oxidative stress, and histone deacetylation in the spine cord tissues after acute cervical spinal cord contusion; 2) evaluate the effect of inhibition of monocarboxylate transporter on prevention of SCI neuroprotection, gene expression, HDACs and oxidative stress; 3) determine the suppression of oxidative stress and changes of histone acetylation after SCI treatments using ketone body metabolism; 4) evalute effects of every-other-day-ketone-diet on neuroprotection, acetylation and suppression of oxidative stress. This study will provide a solid preclinical basis in support of SCI treatment, and pave an innovative nutritional regimen for SCI.

英文关键词： Ketone body metabolism;Spinal cord injury;Neuroprotection;Histone deacetylase;β-hydroxybutyrate