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Role of Slug in Regulation of Hematopietic Stem Cells

Slug 在造血干细胞调节中的作用

基本信息

批准号：
7985277
负责人：
WEN-SHU WU
金额：
$ 5.4万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-10 至 2011-05-09
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) ensure the production of all mature blood cells during homeostatic and regenerative hematopoiesis. It is clearly in the best interests of the organism, therefore, to evolve mechanisms that will protect HSCs from untimely death due to potentially lethal DNA damage. Work from this laboratory has shown that in response to DNA damage, the transcription factor Slug is induced by (-irradiation through p53 and protects committed hematopoietic progenitors from apoptosis triggered by otherwise lethal doses of radiation. Slug exerts this protective effect by repressing Puma, a proapoptotic target of p53. Since Slug is also expressed by HSCs under steady-state conditions, we propose that the radioprotective mechanism we have described for committed hematopoietic progenitors may also operate in HSCs, not only after radiation exposure, but also to maintain HSC functional integrity during steady-state hematopoiesis. Two specific research aims have been devised to test these predictions. First, since Slug-/- mice have a decreased number of functional HSCs under homeostatic conditions, we will establish whether this defect impinges on HSC homing, transition from quiescence to rapid proliferation under conditions of stress, or capacity for self-renewal. Second, we will test the hypothesis that Slug protects normal HSCs from the lethal effects of radiation-induced DNA damage by repressing the cell death protein Puma. On completion of these aims, we will have a much improved understanding of the physiological role of Slug in normal HSCs. If this transcriptional repressor proves important in inhibiting apoptosis, we will consider ways to manipulate its expression and/or function in order to better protect HSCs from genotoxic agents or stress conditions imposed by other factors. One obvious possibility would be to develop strategies to alter the Slug-mediated survival pathway so that it would sustain HSCs during cancer chemotherapy, thus ameliorating the life-threatening consequences of treatment-induced pancytopenia. Lay Summary: Blood stem cells can produce each of different blood cell types in the body. Scientists at the Dana-Farber Cancer Institute have discovered a protein called Slug that may protect these stem cells from damage that could harm their ability to make fresh blood components. If Slug does have this role, it could be an important target molecule in new treatments for blood diseases.

描述(由申请人提供)：造血干细胞(HSCs)确保在动态平衡和再生性造血过程中产生所有成熟的血细胞。因此，进化出保护HSCs免于因潜在的致命DNA损伤而过早死亡的机制显然符合有机体的最佳利益。该实验室的工作表明，作为对DNA损伤的反应，转录因子Slug通过P53被辐射诱导，并保护承诺的造血祖细胞免受致死剂量辐射引发的细胞凋亡。Slug通过抑制Puma发挥这种保护作用，Puma是P53的促凋亡靶标。由于SLUG也在稳态条件下由HSC表达，我们认为我们为承诺的造血祖细胞所描述的辐射防护机制也可能在HSCs中发挥作用，不仅在辐射暴露后，而且在稳态造血过程中保持HSC功能的完整性。已经设计了两个具体的研究目标来验证这些预测。首先，由于Slug-/-小鼠在稳态条件下功能正常的HSC数量减少，我们将确定这种缺陷是否影响HSC的归巢，在应激条件下从静止到快速增殖的转变，或者自我更新的能力。其次，我们将验证这样一种假设，即Slug通过抑制细胞死亡蛋白Puma来保护正常HSCs免受辐射诱导的DNA损伤的致命影响。在完成这些目标后，我们将对鼻塞在正常HSC中的生理作用有一个更好的理解。如果这种转录抑制因子被证明在抑制细胞凋亡方面很重要，我们将考虑控制其表达和/或功能的方法，以便更好地保护HSCs免受遗传毒剂或其他因素施加的应激条件的影响。一种明显的可能性是开发策略来改变鼻涕蛋白介导的生存途径，使其在癌症化疗期间维持HSCs，从而改善治疗引起的全血细胞减少症威胁生命的后果。总结：血液干细胞可以在体内产生不同类型的血细胞。达纳-法伯癌症研究所的科学家们发现了一种名为Slug的蛋白质，它可能会保护这些干细胞免受损害，从而损害它们制造新鲜血液成分的能力。如果鼻涕虫真的有这种作用，它可能会成为血液疾病新疗法的重要靶标分子。