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中文摘要
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死盒解旋酶 41 (DDX41) 是一种已知的核酸传感器,有助于 对逆转录病毒的干扰素反应。 DDX41 属于 RNA 解旋酶家族,具有独特的功能 DEAD/H 盒 (Asp-Glu-Ala-Asp/His) 结构域,其成员涉及 翻译、核糖体生物发生、核质运输、细胞器基因表达和 前mRNA剪接。 DDX41最近也被鉴定为家族性肿瘤抑制基因 和散发性骨髓增生异常综合征/急性髓系白血病(MDS/AML),以及其他 血液系统恶性肿瘤。在 MDS/AML 中,DDX41 被认为与剪接体相互作用 成分并改变剪接,导致肿瘤抑制基因失活或 基因亚型平衡的改变,尽管这是否通过蛋白质-RNA 发生, 蛋白质-DNA 或蛋白质-蛋白质相互作用尚不清楚。我们最近开发了具有 DDX41的floxed等位基因,这将使我们能够首次研究DDX41在造血中的作用 发展与转型。 DDX41 种系敲除在 E10 开发之前就已死亡,但是 基因敲除杂合小鼠完全存活,将用于确定是否 这些小鼠出现骨髓增生异常。我们还生成了删除的条件淘汰赛 造血干细胞(HSC)中的基因。 HSC 将用于研究 DDX41 的作用 在造血谱系分化中。对敲除 HSC 进行 RNA 测序分析 进行,以确定 DDX41 的缺失是否会导致基因表达改变或剪接缺陷。 HSC将用野生型和突变型DDX41转导;特别是,我们将设计 患者衍生的突变以及 DEAD 和解旋酶结构域中的突变,开始确定 这种蛋白质如何在发育和转化中发挥作用。我们建议使用这些小鼠 研究 DDX41 在 HSC 发育中的作用,并确定其机制 它调节骨髓细胞的转化。这些研究可能会加深我们的理解 AML 以及生成用于测试潜在疗法的模型系统。
英文摘要
Dead-box helicase 41 (DDX41) is a known sensor of nucleic acids that contributes to the interferon response to retroviruses. DDX41 belongs to a family of RNA helicases, with distinct DEAD/H box (Asp-Glu-Ala-Asp/His) domains, whose members have been implicated in translation, ribosome biogenesis, nuclear-cytoplasmic transport, organelle gene expression and pre-mRNA splicing. DDX41 was also recently identified as a tumor suppressor gene in familial and sporadic myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), as well as other hematological malignancies. In MDS/AML, DDX41 is thought to interact with spliceosomal components and alter splicing, resulting in the inactivation of tumor suppressor genes or alterations in the balance of gene isoforms, although whether this occurs through protein-RNA, protein-DNA or protein-protein interactions is not known. We recently developed mice with a floxed allele of DDX41, which will allow us for the first time to study DDX41's role in hematopoietic development and transformation. DDX41 germline knockouts die prior to E10 in development, but mice heterozygous for the knockout are completely viable and will be used to determine whether these mice develop myelodysplasias. We have also generated conditional knockouts that delete the gene in hematopoietic stem cells (HSC). The HSCs will be used to study the role of DDX41 in hematopoietic lineage differentiation. RNA Seq analysis on the knockout HSCs will be performed, to determine if loss of DDX41 results in altered gene expression or splicing defects. The HSCs will be transduced with wild type and mutant DDX41; in particular, we will engineer patient-derived mutations as well those in the DEAD and helicase domains, to begin to determine how this protein functions in development and transformation. We propose to use these mice to study the role of DDX41 in HSC development, as well as to determine the mechanism by which it regulates transformation of myeloid cells. These studies are likely to further our understanding of AML as well as to generate a model system for testing potential therapeutics.
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Role of DDX41 in HSC development and MDS/AML
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