巨噬细胞经内质网应激IRE1α通路加速正畸牙移动的机制研究

在骨皮质切开术加速正畸牙移动过程中，炎症微环境发挥重要作用，但其具体机制尚不清楚。课题组前期研究发现，巨噬细胞作为一种关键的免疫调节细胞，可显著影响骨皮质切开加速正畸牙周骨重建进程；同时，巨噬细胞内质网应激感应分子IRE1α介导的未折叠蛋白反应（UPR）对其功能具有调控效应。因此，我们推测在骨皮质切开加速正畸牙移动时，局部炎症微环境激活了IRE1α通路所介导的UPR，改变牙槽骨中巨噬细胞分型和功能，调节正畸牙移动速率。本课题拟开展人群、动物、细胞、分子层面研究，首先建立小鼠骨皮质切开加速正畸模型观察巨噬细胞分型和功能变化，并采用单细胞测序技术分析可能机制；进一步利用IRE1α巨噬细胞特异性敲除小鼠，明确IRE1α调控巨噬细胞亚群分化参与骨皮质切开加速正畸牙移动的作用；最后，探究巨噬细胞IRE1α介导的UPR通路参与调控骨皮质切开加速正畸牙移动的机制。本研究将为临床加速正畸治疗提供新的思路。

Microenvironment plays an important role in corticotomy accelerated orthodontic tooth movement (OTM), but the precise mechanism remains unknown. We previously found that macrophage, as a vital immunoregulatory cell, can significantly affect the progress of corticotomy accelerated bone remodeling. Moreover, the unfolded protein response (UPR) mediated by IRE1α, an endoplasmic reticulum (ER) stress sensing molecule, has a regulatory effect on local macrophages during OTM. Therefore, we hypothesize that during corticotomy accelerated OTM, local microenvironment activates the IRE1α-mediated UPR, which alter the phenotype and function of local macrophages and regulate the rate of OTM. In this study, we propose to investigate the role of IRE1α in OTM using various human, animal, cellular and molecular approaches. Firstly, we establish murine corticotomy accelerated OTM models and we will employ single cell sequencing to analysis the change of macrophages and the potential mechanism. Then to verify the function of IRE1α on macrophages during corticotomy accelerated OTM, we will take advantage of the IRE1α conditional knockout mice. Finally, the underlying mechanism will be revealed. Taken together, the proposed work will provide novel insights for future clinical treatment of accelerated OTM.