多发性骨髓瘤对间充质干细胞初级纤毛结构和功能影响的机制研究

多发性骨髓瘤（MM）与骨髓微环境之间的相互作用会抑制成骨细胞，导致骨破坏的发生，但MM与骨髓间充质干细胞（MSCs）之间的作用方式及其作用机制尚不完全清楚。我们前期通过MM与MSCs共培养后进行单细胞测序发现MSCs细胞的组分和基因表达谱发生明显改变，其中初级纤毛受到显著抑制，有研究提示初级纤毛受损与骨骼异常具有相关性；利用CRISPR/Cas9技术筛选发现MM与MSCs之间相互作用的关键粘附分子CD40；采用中和抗体靶向CD40可阻断MM导致的初级纤毛受损。本课题将从临床标本、细胞和动物水平深入探究MM中CD40对MSCs初级纤毛结构及成骨分化功能产生的影响，并利用CD40中和抗体联合化疗药物检测靶向后的治疗效果，揭示MM骨破坏的新机制，并为临床转化提供理论基础。

The interaction between multiple myeloma (MM) and bone marrow microenvironment can inhibit osteoblasts and lead to bone destruction, but the mode of interaction between MM and bone marrow mesenchymal stem cell (MSCs) and its mechanism are not completely clear. After co-culture of MM and MSCs, we found that the composition and gene expression profile of MSCs cells changed significantly, in which the primary cilia were significantly suppressed, and some studies suggested that the damage of primary cilia was related to bone abnormality; CRISPR/Cas9 technique was used to screen and find that the key adhesion molecule CD40. The damage of primary cilia caused by MM can be blocked by neutralizing antibody targeting CD40. In this study, we will explore the effect of CD40 in MM on primary ciliary structure and osteogenic differentiation of MSCs from clinical specimens, cells and animals, and use CD40 neutralization antibody combined with chemotherapeutic drugs to detect the targeted therapeutic effect, reveal the new mechanism of bone destruction of MM, and provide a theoretical basis for clinical transformation.