线粒体单链DNA结合蛋白1(SSBP1)对多发性骨髓瘤染色体不稳定性的作用和机制研究

多发性骨髓瘤(MM)目前仍无法治愈，染色体不稳定性(CIN)是其发生发展、耐药性获得和预后不良的关键因素，但CIN发生的分子机制尚不清楚。我们前期研究发现，线粒体单链DNA结合蛋白1(SSBP1)是促进不同阶段浆细胞疾病发生、发展且导致患者预后不良的的关键基因，并初步证实高表达SSBP1的MM患者其发生染色体异常的机率明显增高，故我们推测高表达SSBP1可促进骨髓瘤CIN的发生。本项目拟在现有研究的基础上，从临床层面分析SSBP1与骨髓瘤染色体异常及预后的关系，重点运用高通量Hi-C技术、微阵列比较基因组杂交、CRISPR/Cas9､免疫共沉淀和免疫荧光等技术，从分子、细胞和动物体内实验多个层次阐明SSBP1影响分裂中期姐妹染色单体的凝聚力和分裂后期姐妹染色体的分离从而导致CIN发生的机制，进一步揭示MM的发病机制，以期为MM的预后判断和临床治疗提供新靶点和新思路。

Multiple myeloma (MM) remains an incurable malignancy. Chromosomal instability (CIN) is a key factor in the development of disease, acquisition of drug resistance and poor prognosis. However, the molecular mechanism underlying CIN remains unclear. In our previous study, mitochondrial single stranded DNA binding protein 1 (SSBP1) was identified as a key gene that facilitates the development and progression of plasma cell disease at different stages and leads to poor prognosis of patients. MM patients with higher SSBP1 expression may significantly increase the incidence of chromosomal abnormalities. We speculate that high SSBP1 expression may promote CIN in patients with MM. On the basis of existing research, this project will analyze the relationship between SSBP1 and chromosomal abnormalities and that between SSBP1 and prognosis of myeloma from the clinical perspective. More importantly, we will also use Hi-C (High-through chromosome conformation capture) technology, microarray comparative genomic hybridization (CGH), CRISPR/Cas9, immunoprecipitation and immunofluorescence techniques to explore the mechanism of SSBP1 affecting the cohesion of sister chromatids at metaphase and the separation of sister chromosomes at anaphase in molecular, cell and animal studies. The results will further reveal the pathogenesis of MM and provide new target for the prognosis prediction and clinical treatment of MM.