PI3K/AKT/mTOR/S6K信号通路介导HDAC抑制剂调控神经干细胞分化及其在抗痴呆中的作用论证

Histone acetylation is one of the important research areas of epigenetics. Histone acetyltransferase (HAC）and histone deacetylase(HDAC) coordinate the acetylation of histone. Our previous studies have shown that HDAC inhibitors (HDACi) induced the committed differentiation of neural stem cells (NSCs), but its mechanism needs to be further discussed. In recent years, experimental studies hint that mTOR signaling pathway involved in cellular development. Our previous results strongly suggest that PI3K/AKT/mTOR/S6K signaling pathway may be involved in the process of HDACi regulating the directional differentiation of NSCs. From molecular, cellular and animal level, this project is planed to analyze the function and mechanism of HDACi regulating NSCs differentiation and their demonstration against Alzheimer`s disease (AD) via employing the technology and methods of morphology, molecular biology, electric physiology, behavioristics, pharmacology, epigenetics and RNAi. This project not only clarifies the new mechanism of the HDACi inducing directional differentiation of NSCs and provides new targets for differentiation of stem cell, also make great significance for clarifying the pathogenesis of AD and the research and development of target drugs of AD.

组蛋白乙酰化是表观遗传学重要研究内容之一。组蛋白乙酰化转移酶（HAC）和组蛋白去乙酰化酶（HDAC）协调进行着组蛋白的乙酰化。我们前期研究已表明HDAC抑制剂（HDACi）可诱导神经干细胞(NSCs)定向分化，然而其机制有待深入探讨；近年的实验研究提示mTOR信号通路参与了细胞的发育，我们前期结果强烈提示PI3K/AKT/mTOR/S6K信号通路可能参与HDACi调控NSCs的定向分化。本课题拟采用形态学、分子生物学、电生理、行为学、药理学、表观遗传学、RNAi等技术和方法，从分子、细胞和动物水平，解析HDACi调控NSCs分化的作用和机制及其在转基因痴呆鼠中的论证。这不仅阐明了HDACi诱导NSCs定向分化的新机制，为干细胞诱导分化提供新靶点；也对AD发病机理的阐明和AD靶点药物的研发均具有重要意义。

组蛋白乙酰化是表观遗传学重要研究内容之一。组蛋白乙酰化转移酶（HAC）和组蛋白去乙酰化酶（HDAC）协调进行着组蛋白的乙酰化。我们利用HDAC抑制剂（HDACi）作用于干细胞包括神经干细胞(NSCs)和胚胎干细胞(ESCs)，研究表明HDACi可诱导NSCs和ESCs定向分化并探讨了其作用机制；我们研究提示mTOR信号参与了神经干细胞的发育和分化，且通过PI3K/AKT/mTOR/S6K信号参与HDACi调控NSCs的定向分化；同时进一步说明了mTOR信号可能通过影响细胞整体和特定神经元基因Ngn1的表观遗传学修饰（包括DNA甲基化/去甲基化、组蛋白甲基化）从而调控细胞分化（Stem Cell Reports 2017;8(5):1256-1269. 中华生物医学工程杂志，2014，20（6）：423~427），此外，我们也利用HDACi腹腔注射老年痴呆鼠模型（AD），观察到HDACi可逆转或改善AD的功能障碍（Mol Neurobiol. 2015;51(1):300-12.），此研究解析了HDACi调控NSCs分化的作用和新机制；也对AD发病机理的阐明和AD靶点药物的研发均具有重要意义。