Stk40在造血干祖细胞动员中的作用与机制研究

Hematopoietic stem cell transplantation (HSCT) is currently one of the most important therapies for clinically curing malignant hematological diseases. Physiologically, hematopoietic stem cells (HSCs) are rare in peripheral blood. Thus, effective mobilization of HSCs from bone marrow to peripheral blood is of utmost significance. Stk40 is an evolutionally conserved protein containing a serine/threonine kinase domain and participates in mammalian early embryonic development as well as regulates numerous physiological and pathological processes. Our previous work found that Stk40 is involved in intrinsic regulation of hematopoietic stem and progenitor cells (HSPCs), and deletion of Stk40 impairs definitive erythropoiesis, leading to increased cell motility through activating inflammation-associated signaling pathways in the mouse. However, how Stk40 regulates motility of HSPCs remains unknown. Thus, in this project, we plan to further investigate the function and mechanism of Stk40 during mobilization of HSPCs, using Stk40 KO and CKO mice via Transwell, colony forming cell and HSCT assays. Moreover, we collect blood samples and clinical information of inpatients undergoing HSCT to explore STK40 as one potential biomarker of mobilization and transplantation. This study will elucidate the molecular mechanism of HSPC mobilization and Stk40 regulatory networks. Also screening clinically applicable biomarkers helps enhancing mobilization and transplantation outcomes, which can be a fairly good transition from bench to bedside.

造血干细胞移植是目前治疗血液系统恶性疾病的重要方案之一，如何将骨髓中的造血干祖细胞(HSPC)有效动员到外周血是移植成功的关键步骤之一。Stk40含有丝氨酸苏氨酸激酶结构域，参与胚胎早期发育并调控众多生理病理学过程。前期研究发现，Stk40参与调控HSPC生物学特性；缺失Stk40影响小鼠红系定向分化，并激活炎症相关信号通路而导致细胞运动性增强。但其如何调控HSPC的动员过程尚不清楚。为此，本项目拟用现有的Stk40 KO与CKO动物模型，通过Transwell、集落形成实验和造血干细胞移植等揭示Stk40在小鼠HSPC动员中的作用。 同时结合临床供者资料与随访信息，探索STK40作为动员与移植效果生物标记物的潜在可能性。本研究将进一步完善HSPC动员的分子机制。此外，筛选有临床应用价值的生物标记物将有助于增进HSPC动员效果和后续造血干细胞移植成功率，更好地实现基础研究成果的临床转化。

白血病是造血系统最常见的恶性肿瘤，骨髓及其他造血组织中大量白血病细胞无限制地增生并浸润全身各组织和器官，严重危害人类健康。STK40含有丝氨酸苏氨酸激酶结构域，参与胚胎早期发育并调控众多生理病理学过程。前期研究发现，Stk40参与调控小鼠HSPC生物学特性；缺失Stk40影响小鼠红系定向分化，并激活炎症相关信号通路而导致细胞凋亡增强。生物信息学分析结果显示，STK40在白血病细胞中低表达，因此，研究STK40在急性髓系白血病中的作用与机制对于此类疾病的治疗、预防及寻找潜在的治疗靶点与药物具有重要意义。在此基础上，检测白血病细胞系和病人标本中STK40的表达水平并探索STK40作为AML病人诊断和预后标志物的可能性。并借助于生物信息学分析结果，为后续白血病的临床诊断与治疗提供新的思路。