SOX4/LncRNA-ANCR调控间充质干细胞自我更新与成骨分化的机制研究

With the aging process of our population, the increase in the number of senile diseases leads to an increasing social burden. Adult stem cell senescence is one of the important causes of aging. Bone marrow derived mesenchymal stem cells (BMSCs) have the ability to differentiate into osteoblasts, chondrocytes and adipocytes, the decline of its function is closely related to the loss of bone mass in aging process. Transcription factor SOX4 plays an important role in the maintenance of stem cell function. We found that the expression of SOX4 in mouse BMSCs decreased during aging, and was closely related to the decrease of bone mineral density . Further studies on human BMSCs showed that SOX4 regulates LncRNA-ANCR expression. In this project, we intends to use the conditional knockout mice model to clarify the role of SOX4 in BMSCs self-renewal and osteoblast differentiation, study the function of SOX4 on ANCR in human BMSCs during aging. Chromatin Isolation by RNA Purification (ChIRP) technique combined with high-throughput sequencing and mass spectrometry will be used to identify the binding protein and target of ANCR and further analysis the in-depth molecular mechanism of SOX4/ANCR’s function on BMSCs. The results of this project will be helpful to reveal the molecular mechanism of age-related bone loss and provide new ideas for the prevention and treatment of senile disease.

随着我国人口老龄化的进程，老年疾病增多导致社会负担日益加重。成体干细胞衰老是机体衰老的重要原因之一。骨髓来源的间充质干细胞（BMSCs）具有向成骨、软骨和脂肪细胞分化能力，其功能下降与衰老进程中的骨量丢失密切相关。转录因子SOX4对干细胞功能维持非常重要。我们发现，增龄过程中小鼠BMSCs的SOX4表达下降，与骨密度下降密切相关；进一步利用人BMSCs研究发现SOX4调控LncRNA-ANCR表达。本项目拟利用条件敲除小鼠，阐明SOX4对BMSCs自我更新和成骨分化功能的作用及机制；采用人BMSCs为研究对象，研究增龄过程中SOX4对ANCR的调控；利用RNA纯化染色质分离（ChIRP）技术，结合高通量测序和质谱方法，鉴定ANCR的结合蛋白和作用靶点；深入解析SOX4通过ANCR调控BMSCs功能的分子机制。研究成果将有助于揭示增龄性骨量降低的分子机制，为相关老年疾病防治提供了新思路。