骨髓移植治疗遗传性弥漫性白质脑病合并轴索球样变及其机制研究

CSF1R基因突变所致的遗传性弥漫性白质脑病合并轴索球样变(HDLS)是一种青年发病为主，具有严重致残和致死性的遗传性白质脑病。CSF1R是一种Ⅲ型酪氨酸激酶受体，也是单核-吞噬系统信号转导的关键调节因子，参与巨噬细胞的生存、增殖和趋化等。CSF1R突变后，其酪氨酸激酶结构的磷酸化水平下降或丧失，导致下游信号转导的障碍。全世界，共报道了4例进行骨髓造血干细胞移植治疗的HDLS病例。前期，我们成功完成了3例HDLS的移植治疗，患者的认知、运动、影像等均获得改善，说明骨髓移植是目前治疗HDLS唯一可能有效的方法。因治疗机制不明确，缺乏动物研究，无法进一步开展大样本的临床研究。本课题，对HDLS小鼠模型进行骨髓移植治疗，对表型、影像和病理改变进行评估，明确治疗短期和长期效果、最佳治疗时期等，并通过转录组学、蛋白质组学、细胞融合实验、趋化和和增殖实验等方法，明确骨髓移植治疗HDLS的机制。

Hereditary diffuse leukoencephalopathy with spheroids (HDLS), caused by mutations of CSF1R gene, is a rare juvenile-onset hereditary white matter disease characterized by high rates of disability and mortality. Colony-stimulating factor 1 receptor (CSF1R), a Type Ⅲ tyrosine kinase receptor, is a key regulator of signal transduction in the mononuclear-phagocytic system, participating in the survival, proliferation and chemotaxis of macrophages. The mutant CSF1R will lead to decreased or absent phosphorylation level of its tyrosine kinase domain, hindering the downstream signal transduction. Up till now, a total of 4 cases of HDLS have been reported worldwide to benefit from bone marrow hematopoietic stem cell transplantation therapy. In the previous work, we have successfully performed the transplantation on 3 patients of HDLS. As a result, their cognition, motor function and imaging manifestations were significantly improved, suggesting that bone marrow transplantation might be the only effective therapy for HDLS. However, unclear therapeutic mechanisms and lack of evidence from animal experiments limited the development of further clinical studies with a large sample size. Therefore, in this study, we will perform bone marrow transplantation on the HDLS mouse models and evaluated their phenotype, imaging and pathological changes to explore the therapeutic effects in both short and long term and determine the optimal timing of treatment in clinical practice. Furthermore, methods such as transcriptomics, proteomics, cell fusion detection, chemotaxis and proliferation experiments will be applied to clarify the mechanisms of bone marrow transplantation as a therapy for HDLS.