纳米拓扑结构介导FAK/TSC2调控细胞自噬的机制研究

新骨生成能力减缓是骨质疏松症患者种植体脱落的原因之一，然而目前尚无针对性的解决方法。骨质疏松症患者细胞自噬水平下降，而自噬具有调节骨稳态的作用。申请人前期研究发现纯钛表面纳米拓扑结构通过上调自噬促进MC3T3-E1细胞成骨分化，此外过表达FAK会抑制自噬的发生及其介导的成骨过程。由于FAK与TSC2的结合作用参与自噬起始关键因子mTORC1的活化过程，申请人推测，纯钛表面纳米拓扑结构可能通过FAK/TSC2扭转细胞自噬水平，从而促进植体周围骨质疏松症细胞的成骨分化和骨结合。为验证该假设，本项目拟建立骨质疏松大鼠模型和低自噬水平细胞模型，以明确纳米拓扑结构介导FAK/TSC2调控成骨的分子机制,并基于DRIE技术制备不同尺寸的柱状结构，探究细胞黏附间断是否为纳米拓扑结构介导FAK调控成骨的关键因素。该研究将为构建更适用于骨质疏松患者的种植体提供重要参考依据。

In patients with osteoporosis, new bone formation is weakened and the risk of detachment of the implants is increased. Decreased autophagy is one of the important factors that prevents bone formation in patients with osteoporosis. Our previous research indicated that the nanotopography on titanium surface promoted osteogenic differentiation of MC3T3-E1 via up-regulating autophagy. In addition, the overexpression of FAK not only inhibited autophagy, but also hindered the osteogenic property . Since the binding of FAK and TSC2 owned the ability to activate mTORC1，we proposed that titanium nanotopography may reverse the autophagy level through the FAK/TSC2 pathway, which further promote osteogenic differentiation of peri-implant cells under osteoporotic condition. To verify this hypothesis, our study aims to establish an osteoporotic rat model and a low autophagic model in vitro, and identify the underlying mechanism of FAK/TSC2-mediated osteogenesis. Furthermore，the columnar structures of different sizes will be constructed by DRIE technology to explore how the nanostructure indirectly participates in the regulation of osteogenic process mediated by FAK through modulating cell adhesion. This study will provide theoretical evidence for the development of implants that can be adaptable and translational to the needs of patient with osteoporosis.