5: SLUG AS A KEY REGULATOR OF HEMATOPOIETIC STEM CELL SURVIVAL

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 化疗和放疗严重损害造血干细胞（必须终生保护）。因此，提高这些疗法效率的方法应包括增加肿瘤敏感性和/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解剖造血干细胞和祖细胞中的存活信号通路。 我们以前发现了如何鼻涕虫，鼻涕虫/蜗牛家族的锌指转录抑制因子的成员，允许骨髓祖细胞逃避遗传毒性剂的致死作用。在髓系祖细胞中，Slug通过拮抗Puma的p53上调（Puma是BH 3依赖性凋亡途径的促凋亡因子），以细胞自主方式保护小鼠免受γ辐射诱导的死亡。 我们的研究结果进一步暗示Slug作为造血干细胞中的候选关键抗凋亡因子，并且支持数据表明Slug由造血干细胞表达。Slug是否能保护这些重要细胞免于DNA损伤导致的死亡，以及机制如何，还有待确定。为了解决这些问题，我们提出了两个具体目标： 目标1：研究内源性Slug保护造血干细胞免受γ辐射诱导的DNA损伤的致死效应的程度 目的2：研究Slug基因的增强表达是否能增强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