HMGB1通过脂肪合成调控阿尔茨海默病慢性低度炎症的分子机制研究

阿尔茨海默病（AD）是老年人常见的痴呆类疾病，对家庭和社会有沉重的负担。慢性低度炎症(CLGI）是促进阿尔茨海默病（AD）发生和发展的重要因素。维持CLGI需要体内致病因子持续刺激相关细胞产生炎症因子，但体内具体依靠一些什么致病因子维持CLGI尚不清楚。本项目的主要研究内容是：在细胞水平上探索同型半胱氨酸（Hcy）、高迁移率组蛋白1（HMGB1）、脂滴与慢性低度炎症指标之间的相关性；研究HMGB1靶基因在小胶质细胞脂滴形成和CLGI中的作用以及相关分子机制；在AD转基因小鼠模型中，针对以上探索出的新分子靶点进行联合干预，探索逆转CLGI的可行性，通过动物实验，检查AD小鼠血液和脑组织中相关炎症因子的变化；针对AD患者研究Hcy、HMGB1、脂滴与慢性低度炎症指标之间的相关性。完成本项目研究后，将会得到下述重要结果：基本阐明通过HMGB1与胆固醇调节元件结合蛋白1（SREBP1 ）信号通路调控小胶质细胞分泌炎症因子促进CLGI的分子机制，据此筛选出抑制 CLGI 的可能干预靶点；并初步证实 CLGI 的发生和发展是部分AD 患者发病或恶化的重要原因。预期能发表 SCI 收录论文 2 篇（希望影响因子1-3分），北大核心期刊论著 1 篇；参加国内学术会议2 次，参加国际学术会议并进行国际学术交流1次；培养硕士研究生 2 名。 本项目研究的科学意义是：探索高 Hcy 是如何通过 HMGB1/SREBP1 信号通路调控小胶质细胞内的脂肪合成、并研究诱导神经性炎症反应的过程，从而寻找 CLGI 的发生是如何促进 AD 的进展，将有助于 AD 发病机制的阐明和 AD 的防治；本研究以分析慢性神经性炎症为突破口，临床研究结合细胞和动物实验，很可能会发现治疗AD 有价值的干预靶点，将为阻止AD 的发生提供新的思路。

Alzheimer's disease (AD) is a common dementia disease in the elderly, which has a heavy burden on family and society. Chronic low-grade inflammation (CLGI) is an important factor to promote the occurrence and development of Alzheimer's disease (AD). To maintain CLGI, pathogenic factors in vivo need to continuously stimulate related cells to produce inflammatory factors, but the specific factors that the body depends on to maintain CLGI are still unclear. The main research contents of this project are to explore the correlation between homocysteine (Hcy), high mobility group 1 (HMGB1), lipid droplets and chronic low-grade inflammation indicators at the cellular level; to study the role of HMGB1 target gene in the formation of lipid droplets in microglia and CLGI and the related molecular mechanisms; in AD transgenic mice model, the new molecular targets explored above, and to explore the feasibility of reversing CLGI, animal experiments were carried out to examine the changes of related inflammatory factors in blood and brain tissue of AD mice, and to study the correlation between Hcy, HMGB1, lipid droplets and chronic low-grade inflammation indexes in AD patients. After the completion of this project, the following important results will be obtained: basic elucidation of HMGB1 and cholesterol regulatory element binding protein 1 (SREBP1) signaling pathway to regulate microglia to secrete inflammatory factors and promote CLGI, so as to screen out possible intervention targets to inhibit CLGI; and preliminarily confirm that the occurrence and development of CLGI are part cause of AD patient or important pathogenesis. It is expected to publish 2 papers indexed by SCI (1-3 points for impact factor), 1 paper published in core journals of Peking University; and attend 2 domestic academic conferences, participate in international academic conference and conduct international academic exchange once; to train 2 postgraduate students. The scientific significance of this project is to explore how high Hcy regulates fat synthesis in microglia cells through HMGB1/SREBP1 signaling pathway, and to study the process of neuroinflammatory response induction, so as to find out how the occurrence of CLGI promotes the progress of AD, which will contribute to the clarification of the pathogenesis of AD and the prevention and treatment of AD. In this study, the analysis of chronic neuroinflammation as breakthrough, clinical research combined with cell and animal experiments, is likely to find a valuable intervention target for AD treatment, which will provide new ideas for preventing the occurrence of AD.