犬瘟热病毒感染导致破骨细胞功能异常的分子机制研究

Paget's disease of bone (PDB) is a metabolic disorder disease of bone. The main characteristic is hyperactivity of osteoclast, causing rapid dissolution of bone and hyperactive reconstruction, which eventually leads to skeletal deformity and seriously affects the life quality of patients, however, the etiology remains unknown. In previous study, canine distemper virus (CDV) has been found in osteoclasts of a large number of patients, nevertheless, whether CDV infection can cause morphological and functional abnormalities of osteoclasts, which viral proteins and signaling pathways play a key role in this process remains to be clarified. In this study, the osteoclasts of human and mice will be used as in vitro model to study the effects of CDV infection on the morphology, number of nuclei, differentiation efficiency and Calcium absorption capacity of osteoclasts, and also the effects of CDV infection on NF-κB/MAPK/IL-6 signal pathway will be analyzed. The mice with mutant SQSTM1/P62 gene will be used as an in vivo model to study the effects of CDV infection on morphology, Calcium absorption capacity and signal pathway of SQSTM1/P62 gene mutant osteoclast, along with the effects on transformation, composition and density of skeleton in vivo. This study will investigate the mechanism of PDB caused by CDV, and lay a theoretical foundation for the prevention and treatment of PDB.

Paget骨病是一种人的骨代谢紊乱疾病，主要特点为破骨细胞功能亢进，引起骨的高速溶解和快速重建，最终导致骨骼畸形，严重影响患者生活质量，其发病机制一直不详。研究发现，大量患者破骨细胞中存在犬瘟热病毒，但犬瘟热病毒感染能否引起破骨细胞形态和功能异常、哪些病毒蛋白及信号通路在该过程中发挥关键作用等都尚待阐明。因此，本项目拟以人和小鼠的破骨细胞为体外模型，研究犬瘟热病毒感染对破骨细胞的形态、细胞核数量、分化效率及钙吸收能力的影响，并分析病毒对破骨细胞特征性信号通路NF-κB/MAPK/IL-6的影响；进一步以SQSTM1/P62基因突变小鼠为体内模型，分析犬瘟热病毒与SQSTM1/P62基因突变协同对破骨细胞的形态、钙吸收能力、特征性信号通路的影响，以及对骨骼的转化、成分和密度的影响。本研究将深入揭示犬瘟热病毒引起破骨细胞功能亢进导致Paget骨病的机制，为预防和治疗Paget骨病奠定理论基础。

Paget骨病是一种人的骨代谢紊乱疾病，主要特点为破骨细胞功能亢进，引起骨的高速溶解和快速重建，最终导致骨骼畸形，严重影响患者生活质量，其发病机制一直不详。研究发现，大量患者破骨细胞中存在病毒，犬瘟热病毒出现的比例很高，但犬瘟热病毒感染能否引起破骨细胞形态和功能异常、哪些病毒蛋白及信号通路在该过程中发挥关键作用等都尚待阐明。本研究发现，犬瘟热病毒可以通过持续性感染激活NF-κB/MAPK/IL-6信号通路，引起破骨细胞的融合与功能亢进。进一步发现，犬瘟热病毒的囊膜糖蛋白F和H，可不依赖NF-κB/MAPK/IL-6信号通路促进破骨细胞的融合。通过高通量测序分析了犬瘟热病毒持续性感染破骨细胞时的转录组的特征，并初探了小分子药物T705抑制犬瘟热病毒复制的效率及其作用机制。本研究进一步揭示了犬瘟热病毒引起破骨细胞功能亢进导致Paget骨病的机制，为预防和治疗Paget骨病奠定了前期基础。