HMGB1在神经炎症，神经退行死亡和帕金森病形成的分子机制和神经行为学研究

项目名称： HMGB1在神经炎症，神经退行死亡和帕金森病形成的分子机制和神经行为学研究

项目编号： No.31471006

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 高慧明

作者单位： 南京大学

项目金额： 87万元

中文摘要： 帕金森病的炎性发病机制渐被重视。但是，以小胶质细胞激活为特征的神经炎症如何介导数十年的神经退行死亡以及慢性神经炎症是如何维持的这些关键问题亟待深入研究。我们用帕金森病体外模型的研究表明释放到细胞外的核蛋白HMGB1（高迁移率蛋白）诱导慢性神经炎症和神经死亡。本项目以前期的原创性发现为基础，通过从体外实验到小鼠整体水平，系统深入地研究1）小胶质细胞分泌HMGB1机制和调控（翻译后乙酰化修饰及其调控等），2）细胞外HMGB1与Mac1受体结合的机制和动态调控，3）HMGB1诱导野生型和基因工程小鼠帕金森病样神经退行死亡，α-synuclein聚合和内涵体形成，以及运动功能障碍的作用和机理。本项目对帕金森病炎性发病机制的深入研究有望鉴定出新的治疗靶点，为该病的抗炎免疫治疗和神经保护药物的研发提供理论基础，为转换医学提供科学支撑，有望为将来找到治疗神经退行性疾的有效新方法提供有用线索。

中文关键词： HMGB1；神经退行死亡；小胶质细胞；神经炎症；帕金森病

英文摘要： The inflammatory mechanism of neurodegenerative diseases (a group of chronic, progressive neurodegenerative disorders that share a common inflammatory feature) has been increasingly appreciated. However, how microglial activation (the signature event of neuroinflammation) mediates the decades-long neurodegeneration and how chronic neuroinflammation is maintained in neurodegenerative diseases are key questions requiring immediate and extensive investigation. Our recent data generated from in vitro models of Parkinson's disease (PD, the second most common neurodegenerative disease) indicate that extracellular high-mobility group box 1 (HMGB1) might link chronic neuroinflammation to progressive neurodegeneration. HMGB1, a DNA-binding protein, regulates chromatin structure and transcription in nuclei. It is of special interest that extracellular HMGB1 can be passively released by necrotic cells and actively secreted from inflammatory cells. It has been reported that translational modifications (e.g. oxidation, phosphorylation and acetylation) affect the nuclear-cytoplasmic translocation and secretion of HMGB1 in peripheral monocytes and macrophages. What factor(s) governs the active secretion of HMGB1 by microglia remains to be poorly understood. This project will investigate how sirtuin 1 (SIRT1; a NAD+-dependent deacetylase) affects HMGB1 acetylation and active secretion by microglia. Our previous studies showed that extracellular HMGB1 can function as a DAMP (damage-associated molecular pattern molecule) or an alarmin to signal damage occurrence and to initiate inflammatory responses through macrophage antigen complex 1 (Mac-1). This project will further determine the mechanism and the regulation of HMGB1-Mac1 interaction (such as the determination of the key amino acid sequence of their interaction). Moreover, we will for the first time to examine the role of extracellular HMGB1 induces nigral chronic neuroinflammation and PD -like phenotypes (such as dopaminergic neurodegeneration, α-synuclein accumulation and aggregation, formation of cellular inclusions), and movement impairment in wildtype and genetically engineered mice. However, its roles in the regulation of CNS immune response and the development of Parkinson's disease are largely undetermined. We plan to use genetically engineered mice and cell cultures to investigate the cellular and molecular mechanism by which HMGB1 interacts with Mac1 to affect communication between neurons and microglia and development of PD. Results from these studies will identify novel anti-inflammatory therapeutic target and shed new insight into the immune regulation of the CNS and the potential driving force of progressive neurodegeneration. Further development and screening of anti-inflammatory and neuroprotective drugs targeting the identified target(s) identified by this project will provide important mechanistic basis for translational medicine for future clinical trails for neurodegenerative diseases.

英文关键词： HMGB1;neurodegeneration;microglia;neuroinflammation;Parkinson's disease