骨源分泌因子RANKL维持脑稳态的机制研究

近年来多项临床及基础研究报道骨疾病同中枢神经系统疾病密切相关，当骨骼系统出现疾病时，中枢神经系统也表现异常。RANKL是骨骼分泌的重要因子，对调节骨代谢和维持机体稳态发挥重要作用，然而RANKL对中枢神经系统的调节作用和机制尚不清晰。本项目以动物模型为研究对象，结合神经科学技术及骨代谢分析等手段，解析RANKL调节神经系统和维持脑稳态的机制，拟研究：（1）骨源因子RANKL在中枢神经系统的结合靶点，及其受体在中枢神经系统的分布特征；（2）生理病理状态下RANKL对中枢神经回路的调控作用和机制；（3）RANKL相关神经环路对外周交感神经系统调节和维持骨稳态的机制。本研究将：（1）明确骨RANKL在中枢神经系统中的作用靶点；（2）阐明RANKL调节中枢神经回路的作用和分子机制；（3）深入理解RANKL在病理状态下引发情绪障碍和骨丢失的机制，为骨疾病导致的中枢神经异常的干预提供新思路和理论依据。

Recently many studies have demonstrated that the skeletal diseases are closely related with the abnormalities of the central nervous system: the function of the central nervous system display abnormal during the development of the skeletal disease. RANKL is an important bone-derived factor which play crucial roles in regulating the bone metabolism and maintain the body homeostasis, however up to now the function of RANKL in regulating the central nervous system and underlying mechanism is not clear. Our study aims to investigate the mechanism of bone derived RANKL in regulating the central nervous system, using the technique of neural circuits tracing, optogenetics, electrophysiological recording and bone metabolism analysis. We will study: (1) The binding targets of RANKL in the central nervous system, and the distribution pattern of the RANKL receptors in the brain; (2) The regulatory effects of RANKL on the central neural circuits and underlying mechanism; (3) The mechanism of RANKL related neural circuits in regulating the activity of peripheral sympathetic nervous system and maintaining bone metabolism. Our study will illustrate the molecular mechanisms of RANKL in targeting specific brain regions and regulating the function of the central neural circuits; provide evidence in understanding the pathogenesis of brain abnormalities such as mental disorders induced by skeletal disease; and propose a potential strategy to intervene the malfunctions of the central nervous system during the progression of the skeletal disease.