自噬应激对发育期惊厥远期海马线粒体呼吸的影响及调节

项目名称： 自噬应激对发育期惊厥远期海马线粒体呼吸的影响及调节

项目编号： No.81471337

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： 倪宏

作者单位： 苏州大学

项目金额： 70万元

中文摘要： 通常认为自噬主要参与急性脑损伤病理过程，但是最近发现在阿尔茨海默及脑外伤病人脑组织中存在自噬应激（自噬的过度活跃或功能低下），说明在脑损伤的慢性期亦存在自噬信号稳态的破坏，而这种改变的意义有待阐明。我们在前期国家自然科学基金项目中发现发育期惊厥远期大鼠海马和大脑皮层自噬标记蛋白beclin-1表达上调，生酮饮食可抑制其异常高表达。由于生酮饮食主要通过影响线粒体能量代谢发挥作用，因而推测生酮饮食对发育期惊厥性脑损伤的保护作用涉及对线粒体呼吸和自噬信号通路的调节。本项目拟通过体内和体外发育期惊厥模型进一步探讨自噬应激和线粒体呼吸障碍在发育期惊厥所致远期惊厥阈下降、脑兴奋性提高和海马神经可塑性改变中的作用；进而验证作用于自噬通路药物能够通过调节自噬应激阻止远期线粒体呼吸功能障碍和海马病理损伤；并采用生酮饮食进一步验证上述假设，籍此证明维持自噬信号通路稳态是改善发育期惊厥后远期神经功能损伤的靶点。

中文关键词： 发育期惊厥；海马；自体吞噬；线粒体呼吸；生酮饮食

英文摘要： It has long been recognized that that autophagy is mainly involved in the pathological process of acute brain injury. However, since autophagy stress (over-increased or decreased autophagy) is seen in brain specimens from patients with Altheimer's disease (or patients with traumatic brain injuries)-related pathology vs. those without, it is possible that disrupted autophagy signal exists in the chronic phase of brain injury. But the functional consequences of autophagy stress need to be sorted out in further experimental studies. We have recently discovered long-term up-regulated expression of autophagy marker beclin-1 in rat hippocampus and cerebral cortex following develpmental seizures, which could be blocked by ketogenic diet (supported by the National Natural Science Foundation of China, 30870808). Considering the fact that ketogenic diet achieves its neuroprotective effect mainly by influencing the mitochondrial energy metabolism, it is reasonable to speculate that autophagy/ mitochondrial respiration signaling pathways are involved in the process of neuroprotection by ketogenic diet. In the present project using in vivo and in vitro developmental seizure models, we sought to determine the role of autophagy stress and mitochondrial respiratory disorder in the pathophysiology of developmental seizure-induced declined seizure threshold, elevated brain excitability and aberrant changes of hippocampal neural plasticity. We will also verify the notion that autophagy regulating drugs could prevent the forward mitochondrial respiratory dysfunction and pathological injury of hippocampus through adjusting autophagy stress. Furthermore, we will further verify the above hypothesis by using the intervention method of ketogenic diet. After the experiments we might propose a new point of view that maintaining autophagy signal pathways in steady state is the therapeutic target by which to inhibit developmental seizure-induce functional impairment.

英文关键词： developmental seizures;hippocampus;autophagy;mitochondrial respiration;ketogenic diet