新型椎间盘退变动物模型的构建及其应力生物学的机制研究

Intervertebral disc degeneration (IDD) is the leading cause of the chronic low back pain, but the precise mechanism still unclear. Overload was thought a important factor of the IDD, however, relative studies were restrained by the lack of an ideal mechanical animal model. Previous study revealed the differences of the IDD between the older and young patients, suggested that overload contributed the progression of the IDD via different mechanisms. In our previous study, we established a novel, non-invasive and effective bipedal murine model of the IDD. Specifically, when a mouse is placed into a limited space with water, the animal will actively assume a bipedal posture for several hours. this novel model integrated the mechanical signaling with the biological signaling of the intervertebral disc cells, eventually contributed to the progression of the IDD. mTORC1 signaling pathway modified series important physiological functions included the mechanical signal transduction, but the underlying mechanism required further investigation. In our previous study, we established the mTORC1-related gene-modified mice. This study intends to further study the mechanism of the overload regulated the IDD by the methods of the novel animal model and gene-modified mice. Clarifying the characteristics and the potential transduction pathways of the IDD contributed by overload, provide new perspective in the awareness and prevention of IDD.

椎间盘退变是导致慢性腰痛的首要原因，但具体机制尚不清楚。过度应力被认为是促进椎间盘退变发展的重要因素，但是缺乏理想的力学动物模型以支持相关研究。既往研究报道了老年患者与年轻患者椎间盘退变的差异性，提示过度应力能通过衰老以外的机制促进椎间盘退变。本课题组的前期研究构建了一种新型、无创、有效的小鼠双足站立模型。小鼠被置于有限的涉水空间内将选择自主站立，使力学信号与椎间盘细胞的生物学信号在体内条件下结合，加快椎间盘退变进程。mTORC1信号通路参与调节众多生理功能，包括力学信号转导，但具体机制不详。本课题组前期研究构建并繁育了该信号通路相关基因修饰小鼠。因此，在前期基础之上，本课题组拟将基因修饰小鼠联合新型力学模型，深入探讨mTORC1信号通路调控力学转导的具体机制，研究并明确过度应力的作用特点和过度应力导致椎间盘组织退变的其他信号转导途径，从更深层面预防IDD和治疗椎间关节退变引起的腰痛。

椎间盘退行性疾病与慢性腰痛和椎间盘突出症密切相关，可造成劳动力丧失甚至残疾，给社会经济造成沉重负担。研究表明，过度应力是椎间盘组织退变（Intervertebral Disc Degeneration，IDD）的主要危险因素，在椎间盘退变中起关键作用。既往研究提示老年患者与年轻患者椎间盘退变存在差异性，提示过度应力可能通过衰老以外的机制促进椎间盘退变。课题组前期研究构建了一种新型、无创、有效的小鼠双足站立模型，为过度应力致IDD的机制研究提供有效工具。..本研究借助前期构建的新型双足站立小鼠模型，对老龄IDD及应力IDD小鼠模型进行机制探究。研究结果显示，老龄小鼠IDD模型的脊柱运动单元退变与细胞衰老密切相关；应力IDD模型的脊柱运动单元退变由关节突关节启动，成功模拟了始发于脊柱后方的椎间盘退变。后续结合小鼠双足站立模型与腰椎失稳模型进行联合造模，联合造模组小鼠出现明显腰痛行为学改变且椎间盘退变程度显著升高。进一步研究显示，联合造模组小鼠除关节突关节出现退变外，还伴随软骨终板退变程度显著增加及疼痛因子表达上调；临床常用止痛药物可改善小鼠运动能力及下调疼痛因子表达。本研究证实，新型腰痛小鼠模型具有显著的行为学改变及组织学变化，可较好模拟腰痛等椎间盘退变相关病理表现，有望为椎间盘退变及腰痛的防治提供新的靶点。