microRNA-17~92基因簇调控造血干细胞的分子与遗传机制

Hematopoietic stem cells (HSCs)are capable of self-renewing and replenishing hematopoietic system in the lifetime, and tightly regulated by the mechanisms that maintain a balance between self-renewal, differentiation, quiescence and death. However, understanding the role of microRNAs in HSCs remain limited. Our preliminary study of miR-17~92 shows that long term-HSCs (LT-HSCs) are increased in miR-17~92-deficient mice, but reduced in miR-17~92 overexpressed mice. The knockout of the miRNA cluster compromises competitive repopulating activity of HSCs. Therefore, we propose to study the role of miR-17~92 in the regulation of HSCs. The proposed study includes three specific aims: (1) to further characterize cellular defects (e.g. self-renewal, differentitation, quiescence and death) in miR-17~92-deficient or -overexpressed mice; (2) to determine what role the individual microRNAs of the miR-17~92 cluster play in the regulation of HSCs; (3) to identify and characterize downstream genes targeted by the miR-17~92 miRNAs in the regulation of HSCs. Our proposed study will improve our understanding of HSC regulation and the role of microRNAs in stem cell regulation.

造血干细胞（HSCs）自我更新、分化、静息与凋亡的调控是维持HSC和造血系统稳态平衡的关键。除了蛋白质信号分子以外，目前仅知道有限的几个microRNAs参与了HSC的调控。我们开展了miR-17~92基因簇对HSC调控的研究。初步发现，长期HSCs（真正的HSCs）在miR-17~92敲除小鼠中增加，而在miR-17~92过表达小鼠中减少。该基因簇敲除也抑制了HSC的竞争性骨髓重建能力。因此，我们申请进一步阐明miR-17~92基因簇对HSCs的调控。本申请包括3个关键目标：（1）揭示miR-17~92敲除和过表达对HSC自我更新、分化等细胞生物学特性的影响，（2）确认该基因簇中单个miRNA对HSC的功能影响，（3）研究该基因簇调控HSC的下游分子机制。本课题的发现将增进我们对HSC调控的理解，并拓宽对miRNA在干细胞调控中的认识。