PROJECT 10: SLUG AS A KEY REGULATOR OF HEMATOPOIETIC STEM CELL SURVIVAL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Slug是一种转录抑制因子，在多能造血干细胞(HSCs)中表达。通过对同时缺乏Slug和P53或Slug和Puma的小鼠的研究，我们已经确定Slug作用于P53下游和Puma上游，控制体内暴露于遗传毒性应激的髓系祖细胞的命运。这些发现表明，在造血祖细胞对基因毒性应激的反应中，鼻涕虫具有重要的抗凋亡作用。然而，这些发现还不能直接了解Slug在保护多能造血干细胞(HSCs)免受DNA损伤而死亡方面的作用。虽然我们知道内源性slug在长期和短期再生的造血干细胞(HSCs)中都有表达，但它在HSCs调节中的作用仍未确定。因此，我们将解决这些关键问题：(I)在稳态条件下，段塞对于维持HSC的完整性是必不可少的吗？如果是，通过哪种机制(S)？(Ii)在基因毒性应激条件下，Slug是否在调节HSCs自我更新中起重要作用？

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Slug is a transcriptional repressor that is expressed in pluripotent hematopoietic stem cells (HSCs). By studying mice deficient for both Slug and p53 or Slug and Puma, we have established that Slug acts downstream of p53 and upstream of Puma to control the fate of myeloid progenitor cells exposed to genotoxic stress in vivo. These findings implicate a vital anti-apoptotic role for Slug in the response of hematopoietic progenitors to genotoxic stress. However, these findings do not yet provide direct insight into the role of Slug in the protection of pluripotent hematopoietic stem cells (HSCs) from death due to DNA damage. Although we know endogenous Slug is normally expressed in both long- and short-term repopulating hematopoietic stem cells (HSCs), its roles in regulation of HSCs remain to be established. Thus, we will address these critical questions: (i) Is Slug indispensable for maintaining the integrity of HSC under steady-state conditions and, if so, by which mechanism(s)? (ii) Does Slug play an essential role in regulating HSCs self-renewal under genotoxic stress conditions?