基于一种新的造血干/祖细胞(HSPC)衰老模型研究刺五加多糖抗HSPC衰老的作用及其mRNA剪接机制

造血衰老表现为恶性髓系血液病的增加、机体衰老和免疫功能障碍等。故开发抗造血衰老的药物对防治相关疾病有重要意义。造血干/祖细胞（HSPC）衰老是决定造血衰老的首要因素。本研究利用我室首创的一种可快速简便地大量获得衰老HSPC的细胞模型，基于“肾主藏精而化血”理论提出刺五加多糖抗HSPC衰老的研究，并借鉴最新报道“造血衰老的变化本质上与骨髓增生异常综合征（MDS）非常类似”基于MDS模型小鼠进行体内验证。此外，鉴于我们蛋白组学数据“衰老HSPC中mRNA剪接途径变化显著”及“组蛋白甲基化对RNA剪接过程有调控作用”的报道，本项目运用chip-seq、RNAi等技术结合mRNA剪接抑制剂、组蛋白去甲基化酶抑制剂研究HSPC衰老的mRNA剪接机制及其组蛋白赖氨酸甲基化调节。本课题旨在开发抗HSPC衰老及其相关疾病MDS的药物并探明HSPC衰老的mRNA剪接机制，为“益精补血”提供新的科学依据。

Hematopoiesis aging is manifested as an increase in myeloid malignancies, aging and immune dysfunction. Therefore, discovering hematopoiesis aging drugs bears great significance to control the related diseases. HSPC aging is the primary factor of hematopoietic senescence. This research will make use of a model created by our team by which a lot of senescent HSPCs can be obtained quickly and easily, based on the theory of "kidney dominants the storage of essence and transform into blood", to observe the effect of ASPS on HSPC aging. Combined with the recent research finding“The changes observed during hematopoietic aging are qualitatively similar to those that occur in MDS”, we will further study it with MDS model mice in vivo. In addition, based on our Proteomic data“mRNA splicing was significantly altered in the aging model group compared with the young group”and the relevant reports“Histone methylation plays an important role in the regulation of mRNA splicing”, we will use the molecular techniques such as chip-seq, RNAi and the inhibitors of mRNA splicing, histone lysine demethylases to study mRNA splicing mechanism of HSPC senescence and the regulation of histone lysine methylation modification. The purpose of this project is to discover the drugs for HSPCs aging and HSPCs aging related diseases such as MDS, further explore mRNA splicing mechanism of HSPC aging, also provide new scientific basis for “Nourishing kidney essence and enriching blood”.