Role of Slug in Regulation of Hematopietic Stem Cells

描述（由申请人提供）： 造血干细胞（HSC）确保在稳态和再生造血过程中产生所有成熟血细胞。因此，很明显，为了生物体的最大利益，进化出一种机制来保护HSC免于由于潜在的致命DNA损伤而过早死亡。该实验室的工作表明，在对DNA损伤的反应中，转录因子Slug通过p53被α-辐射诱导，并保护定向造血祖细胞免受由致命剂量的辐射引发的凋亡。Slug通过抑制Puma（p53的促凋亡靶点）发挥这种保护作用。由于蛞蝓也表达的造血干细胞在稳态条件下，我们建议，我们所描述的辐射保护机制，致力于造血祖细胞也可以在造血干细胞，不仅在辐射暴露后，但也保持造血干细胞功能的完整性在稳态造血。两个具体的研究目标已经被设计来测试这些预测。首先，由于Slug-/-小鼠在稳态条件下具有减少的功能性HSC数量，我们将确定这种缺陷是否影响HSC归巢，在应激条件下从静止到快速增殖的转变，或自我更新的能力。第二，我们将测试的假设，蛞蝓保护正常的造血干细胞的辐射诱导的DNA损伤的致死作用，通过抑制细胞死亡蛋白Puma。在完成这些目标后，我们将对Slug在正常HSC中的生理作用有更好的理解。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，我们将考虑如何操纵其表达和/或功能，以便更好地保护HSC免受遗传毒性剂或其他因素施加的应激条件的影响。一个明显的可能性是开发改变Slug介导的存活途径的策略，以便在癌症化疗期间维持HSC，从而改善治疗诱导的全血细胞减少症的危及生命的后果。 血液干细胞可以在体内产生各种不同的血细胞类型。Dana-Farber癌症研究所的科学家们发现了一种名为Slug的蛋白质，它可以保护这些干细胞免受损害，这种损害可能会损害它们制造新鲜血液成分的能力。如果Slug确实具有这种作用，它可能是血液疾病新疗法的重要靶分子。

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.