5: 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。 化疗和放射治疗严重损害了造血干细胞(必须终生保护)。因此，提高这些疗法的效率的方法应该包括提高肿瘤敏感性和/或降低对这些关键干细胞的毒性的措施。后一种方法需要仔细剖析造血干细胞和祖细胞中的存活信号通路。 我们之前发现了Slug是锌指转录抑制因子Slug/Snail家族的成员，它是如何允许髓系祖细胞逃避基因毒剂的致命影响的。在髓系祖细胞中，Slug通过拮抗P53‘S上调Puma的表达来保护小鼠免受伽玛辐射诱导的死亡，Puma是一种只有BH3才有的线粒体依赖的凋亡途径的前凋亡因子。 我们的发现进一步表明，在造血干细胞中，Slug是一个候选的关键抗凋亡因子，支持数据表明Slug是由造血干细胞表达的。Slug是否保护这些基本细胞不会因DNA损伤而死亡，以及机制如何，仍有待确定。为了解决这些问题，我们提出了两个具体目标： 目的1：研究内源性鼻涕虫在多大程度上保护造血干细胞免受伽马辐射诱导的DNA损伤的致死效应 目的2：研究增强表达Slug是否增强了造血干细胞对致死剂量辐射的保护作用

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. Chemotherapy and radiation therapy heavily damage hematopoietic stem cells (which must be protected throughout life). Approaches for improving efficiency of these therapies therefore should include measures to either increase tumor sensitivity, and/or reduce toxicity to these critical stem cells. The latter approach requires a careful dissection of survival signalling pathways in hematopoietic stem and progenitor cells. We previously discovered how Slug, a member of the Slug/Snail family of zinc-finger transcriptional repressors, allows myeloid progenitor cells to evade the lethal effects of genotoxic agents. In myeloid progenitors, Slug protects mice from gamma radiation-induced death in a cell autonomous manner by antagonizing p53's upregulation of Puma, a BH3-only proapoptotic factor of the mitochondria-dependent apoptosis pathway. Our findings further implicate Slug as a candidate key antiapoptotic factor in hematopoietic stem cells, and supporting data indicate that Slug is expressed by hematopoietic stem cells. It remains to be established whether Slug protects these essential cells from death due to DNA damage, and mechanistically how. To address these questions, we proposed two specific aims: Aim 1: Investigate the extent to which endogenous Slug protects hematopoietic stem cells from the lethal effects of gamma-radiation induced DNA damage Aim 2: Investigate whether enforced expression of Slug enhances protection of hematopoietic stem cells against lethal dose irradiation