LncRNA BDNF-AS-EZH2/PRC2-H3K27me3调控BDNF表达 参与脑缺血诱导神经突起失营养性变

Formation of dystrophic neurites (DN) is an early event in the pathogenesis of many age-related neurodegenerative diseases especially Alzheimer’s disease, while the underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an essential role in survival and regeneration of neurons and their neuritic processes. We have shown that microvascular injury can induce perivascular neuritic dystrophy, while pilot study for this project indicated upregulation of lncRNA BDNF-AS along with downregulation of BDNF, pointing to a potential BDNF-mediated signaling pathway involved in the pathogenesis of neuritic dystrophy. Further more, pilot study showed upregulation of EZH2/PRC2 and H3K27me3 of BDNF, therefore we speculate that“LncRNA BDNF-AS-EZH2/PRC2-H3K27me3”pathway may plays an important role in the expression of BDNF induced by ischemia. we propose to examine the role of BDNF in ischemia-induced formation of dystrophic neurites using both in vivo and vitro experiment models, and explore the associated upstream and downstream signaling partners and their interplay with cell and molecular biology methods. The proposed investigation might reveal novel molecular targets to intervene the pathogenesis of dystrophic neurites in neurodegenerative diseases.

失营养性神经突起（DN）是多种神经退行性疾病特别是阿尔茨海默病出现的早期病理改变，但其发生机制不明。脑源性神经营养因子（BDNF）是维持神经元和突起生长与再生关键物质。我们前期研究显示脑微小血管损伤可诱导DN形成，预实验发现脑缺血上调长链非编码脑源性神经营养因子反义RNA（LncRNA BDNF-AS）表达并伴随BDNF表达下降，这提示BDNF介导DN病变的分子调控通路。预实验进而发现，脑缺血条件下 BDNF相关调控分子EZH2/PRC2和H3K27me3表达上调，推测LncRNA BDNF-AS-EZH2/PRC2-H3K27me3信号轴改变调控BDNF表达变化。本项目拟通过体内外实验探讨BDNF参与脑缺血致DN形成与发展，并结合细胞生物学和分子生物学技术进一步揭示调控BDNF表达的信号分子及调控关系。本项目将为通过干预DN形成途径防治神经退行性变提供新的思路与分子靶标。

该项目中，我们主要围绕阿尔茨海默病病理改变与分子机制以及药物干预等进行探讨。主要研究了脑微血管损伤/缺血缺氧条件下神经突起失营养性变神经病理改变相关分子与机制，我们发现脑缺血和缺氧引起神经突起失营养性变，BDNF表达下调，lncRNA-BDNF-AS表上调，lncRNA-BDNF-AS可能与UBA52、RAB3GAP2、NKAP、TBK1、RAB1A和RPL3B等蛋白存在互作关系，lncRNA-BDNF-AS可能通过绑定自噬和凋亡相关蛋白影响神经细胞功能。同时基于缺血缺氧引发脑内炎性病变原理我们发现395个lncRNA及123个mRNA可能参与LPS诱导的脑内炎性病变的发生发展。我们进而发现药物雷公藤苷（TG）通过抑制IκBα和p38的磷酸化来改善Aβ25-35诱导的小鼠脑内炎症，661个差异表达的lncRNA，503个mRNA和13个miRNA可能与TG的抗炎作用相关。我们也进行了神经系统AD、PD疾病等复杂疾病科学问题的生物信息学系列探索。项目还支持了本学科密切相关的研究。该项目共支持发表SCI论文14篇，CSCD论文1篇。