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

5：蛞蝓作为造血干细胞存活的关键调节因子

• 批准号: 8360267
• 负责人: WEN-SHU WU
• 金额: $ 23.59万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360267
• 关键词: Address; Apoptosis; Cell Death; Cell Survival; Cells; Centers of Research Excellence; Cessation of life; DNA Damage; Data; Dissection; Dose; Family; Funding; Gamma Rays; Grant; Hematopoietic; Hematopoietic stem cells; Life; Measures; Mitochondria; Mus; Mutagens; Myelogenous; Myeloid Progenitor Cells; National Center for Research Resources; Principal Investigator; Puma; Radiation Induced DNA Damage; Radiation therapy; Regenerative Medicine; Research; Research Infrastructure; Resources; Signal Pathway; Snails; Source; Stem cells; Toxic effect; Transcription Repressor/Corepressor; United States National Institutes of Health; Up-Regulation; Zinc Fingers; chemotherapy; cost; improved; irradiation; member; progenitor; slug; stem; stem cell biology; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 signaling 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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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： 目的1：研究内源性Slug在多大程度上保护造血干细胞免受致死性损伤。 γ辐射诱导的DNA损伤效应 目的2：研究Slug的增强表达是否增强造血干细胞的保护作用 抗致死剂量辐照