急性缺血性卒中（AIS）后线粒体早期可从星形胶质细胞转运至神经元，启动内源性保护机制。但缺血缺氧状态下葡萄糖摄取及利用失衡会导致线粒体功能障碍。葡萄糖转运体（GLUTs）介导葡萄糖摄取是保证细胞存活的关键因素之一，LRP1可调控GLUTs，但在AIS领域研究甚少。LRP1下游核心靶点p-AKT可促进磷酸戊糖途径（PPP）提高葡萄糖在缺血缺氧状态下利用效率！我们前期发现LRP1可被apoE拟肽激活，且apoE拟肽可改善脑创伤后葡萄糖摄取。据此我们提出AIS后apoE拟肽/LRP1通过增加葡萄糖摄取，调控PPP途径，保障转运及自身线粒体功能，最终促进神经细胞存活的科学假设。拟通过AIS体内外模型，运用PET/CT、13C标记等技术，结合代谢组学及线粒体功能等多角度阐释其机制。本课题是前期工作的拓展及深入，不仅可揭示LRP1调控AIS后线粒体能量代谢的核心机制，更有望为临床治疗提供新的干预策略。

Mitochondria, as the powerhouse of cells, play a critical role in cell energy homeostasis and are thus inevitably involved in the ischemic neuronal death. Functional mitochondria transfer from astrocytes to ischemic-injured neurons may contribute to endogenous neuroprotective and neurorecovery mechanisms after acute ischemic stroke (AIS). Neurons rely on oxidative glucose metabolism, but the metabolic adaptations during stroke have remained largely enigmatic. Glucose uptake and utilization disorders caused by ischemia and hypoxia could lead to severe energy supply deficiency of mitochondria. Previously study demonstrated that low density lipoprotein receptor-related protein 1 (LRP1) is required for cell survival by interacting with the glucose transporters (GLUTs) in the brain and regulating glucose uptake. The specific role of LRP1-mediated cerebral glucose uptake in AIS, however, remains poorly understood. We have recently shown that activation of LRP1 by the apoE-mimic peptide shows neuroprotective effects. We also indicated that apoE-mimic peptide increases cerebral glucose uptake after acute brain injury. Notably, phosphorylated AKT (p-AKT) is the key target of LRP1. Activation of p-AKT protects against brain ischemia by shunting glucose into the oxidative pentose phosphate pathway (PPP), thereby improving oxygen radical detoxification and securing redox homeostasis. Based on previous findings, we hypothesize that LRP1 could modulate mitochondrial function via glucose uptake and PPP, thereby promoting neuronal survival. Using strategies including 18F FDG PET/CT, 13C-NMR, metabolomics analysis as well as mitochondrial function measurement, the following experiments are designed: 1) to investigate the role of LRP1 on mitochondrial function in wild type and LRP1-/- mouse MCAO model, and further identify the neuroprotective effects of LRP1 ligand apoE-mimetic peptide. 2) to evaluate the regulatory effects of LRP1 and apoE-mimetic peptide on cerebral glucose uptake and PPP in wild type and LRP1-/- mouse MCAO model. 3) to explore the effects and regulatory mechanisms of LRP1 and apoE-mimetic peptide on glucose uptake, PPP and mitochondrial function via murine astrocyte/neuron primary culture. The current project aims to reveal the mechanism and regulation of LRP1-mediated glucose uptake in improving mitochondrial function after AIS. This project is not only the continuation and development of our previous studies, but also an intensive study of the mechanism of energetic metabolism post AIS, which may make a great significance for clinical therapeutic strategies.