基于fMRI/PET活体成像研究骨关节炎肾虚证下丘脑-软骨下骨神经环路动态变化的调控机制

Osteoarthritis (OA) a common disease affects millions of middle-aged and elderly health and it is of great importance to understand its pathogenesis for the improvement of traditional Chinese medicine (TCM) clinical effects. Based on the former solid works, the kidney deficiency is the pathological foundation of OA. Marrow insufficiency and kidney deficiency leads to the malnutrition of bone and brain contributed to bone metabolism of the central nervous system regulation imbalance and Gu-Wei of subchondral bone that relates to the function disorder of hypothalamus-subchondral bone. However, it is a burning issues that the dynamic regulatory mechanism of kidney deficiency neural circuit in vivo. Therefore, a rat model of OA kidney deficiency using by the natural aging and modified Hulth's method will be established to do the following researches. (1) From the changes of functional connectivity networks and metabolic characteristics in hypothalamus- subchondral bone by the fMRI/PET in vivo imaging, it explores the regulation mechanism of dynamic changes of kidney deficiency neural circuit. (2) From the changes of neuropeptide neurons type in hypothalamus-subchondral bone, it explores the structural basis of kidney deficiency neural circuit. (3) From the changes of neuropeptide type in hypothalamus-subchondral bone, it explores the control targets of kidney deficiency neural circuit. (4) Using Bushen Zhuangjin Decoction treatment, it provides an experimental evidence for the syndrome differentiation and treatment by regulating kidney depended on prescriptions corresponding to syndromes. These works are to enrich the kidney deficiency pathogenesis and furtherly improve the objective research of treatment by regulating kidney providing a scientific basis for the dynamic evaluation system of TCM diagnosis and treatment in OA.

骨关节炎是严重影响中老年人健康的常见疾病，明确本病的病机是提高中医疗效的关键。课题组初步揭示骨关节炎以肾虚为基础，肾虚髓亏，骨失所充，脑失所养，则骨代谢中枢神经调控失衡，引发软骨下骨痿，与下丘脑-软骨下骨功能网络失调有关，而在活体状态下肾虚神经环路的调控机制是亟待解决的科学问题。本研究以自然衰老与改良Hulth法建立骨关节炎肾虚证大鼠模型为研究对象：（1）从fMRI/PET活体成像，观察下丘脑-软骨下骨功能网络、代谢特征的变化，探讨肾虚神经环路动态变化的调控机制；（2）从调控下丘脑-软骨下骨的肽能神经类型，探讨肾虚神经环路的结构基础；（3）从连接下丘脑-软骨下骨信号转导的神经肽种类，探讨肾虚神经环路的调控靶点；（4）采用补肾壮筋汤干预，从方证互参角度为肾虚辨识与从肾论治提供实验依据。旨在丰富肾虚的病机理论，完善从肾论治骨关节炎的客观化研究，为建立骨关节炎中医诊疗的活体评价体系提供科学基础。

骨关节炎常见于中老年人，已成为严重的公共健康问题，明确本病的病因病机，有助于提高中医临床疗效。因此，本项目以骨关节炎的动物模型与细胞模型为研究对象，采用病症结合、方证对应的方法，从组织、细胞、分子等多维度，初步明确下丘脑-软骨下骨交互作用参与骨关节炎肾虚证的形成过程。.结果显示：（1）基于网络药理学，初步验证补肾壮筋汤治疗骨关节炎的多向药理学特点，初步明确下丘脑-软骨下骨交互作用参与骨关节炎的病理过程。（2）从疼痛行为、组织形态、蛋白表达的变化，初步验证破骨细胞活性增强引起软骨下骨重塑异常与骨关节炎疼痛相关；采用悬液芯片、高通量靶标代谢组学，初步揭示炎性因子、神经递质是调节下丘脑-软骨下骨交互作用的关键信号分子；采用fMRI活体成像，初步阐明感觉皮层、运动皮层、听觉皮层、纹状体、扣带回、海马、丘脑等脑区功能连接变化，是骨关节炎肾虚神经环路的功能基础。（3）从疼痛行为、软骨下骨组织形态与疼痛相关神经肽及受体表达的变化，初步明确软骨下骨重塑异常诱导感觉神经增加，参与调节骨关节炎的疼痛；采用fMRI活体成像、活体荧光示踪，初步揭示软骨下骨重塑异常诱导感觉神经增加是激活骨关节炎疼痛脑神经环路的关键诱因；采用TMT定量蛋白质组学、生物信息学，初步阐明软骨下骨重塑异常诱导感觉神经激活骨关节炎疼痛脑神经环路的分子机制，进一步诠释“肾主骨生髓通于脑”的科学内涵，为研究骨关节炎肾虚证的微观辨识与活体评价提供方法学借鉴。.本项目获中国中西医结合学会科学技术奖三等奖1项；发表论文7篇，其中SCI论文2篇；培养硕士研究生3名。