The role of NAMPT/SIRTs signaling in hematopoietic differentiation

NAMPT/SIRTs 信号在造血分化中的作用

• 批准号: 391926187
• 负责人: Professorin Dr. Julia Skokowa, Ph.D.
• 金额: --
• 依托单位: Innere Medizin II: Onkologie, Hämatologie, Klinische Immunologie, Rheumatologie und Pulmologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/391926187?language=en
• 关键词: role; NAMPT; SIRTs; signaling; hematopoietic

Inducible pluripotent stem (iPS) cells are reprogrammed somatic cells with embryonic stem (ES) cell-like characteristics produced by the introduction of specific transcription factors (Oct 3/4, Sox2, Klf4, with or without c-MYC) into partially or fully differentiated somatic cells (e.g. fibroblasts, CD34+ bone marrow hematopoietic cells, keratinocytes from plucked human hair). Investigations using the iPS cells model can help to elucidate the processes of lineage specification and differentiation of several hematopoietic lineages. We have recently reported that nicotinamide phosphoribosyltransferase (NAMPT)-NAD+-SIRT1 pathway played an important role in G-CSF-induced myeloid differentiation of CD34+ hematopoietic cells in vitro and in vivo. NAMPT is a rate-limiting enzyme, which converts Nicotinamide into NAD+ and activates NAD+-dependent protein deacetylases, Sirtuins. Sirtuins are well known as lysine deacetylases for histones and numerous transcription factors. Recent reports demonstrated the importance of SIRT1 in the maintenance of pluripotency and differentiation of ES and iPS cells. However, less is known about the role of NAMPT and sirtuins in the hematopoietic and myeloid differentiation of iPS cells. The aim of the project is to delineate the role of NAMPT-NAD+-Sirtuins pathway in vitro in the hematopoietic differentiation of human iPS cells including early-stage of hematopoiesis and myeloid cell differentiation processes and in vivo in zebrafish model.

可诱导的多能茎（IPS）细胞是通过引入特定转录因子（10月3/4，SOX2，KLF4，或不带C-Myc）引入的细胞（ES）细胞（ES）细胞（ES）细胞样细胞的重编程，并部分或完全不同 头发）。使用IPS细胞模型的研究可以帮助阐明几种造血谱系的谱系规范和分化的过程。我们最近报道说，烟酰胺磷酸糖基转移酶（NAMPT）-NAD+ -SIRT1途径在G-CSF诱导的CD34+造血细胞的髓样分化中起着重要作用。 NAMPT是一种限速酶，可将烟酰胺转化为NAD+，并激活NAD+依赖性蛋白脱乙酰基酶Sirtuins。 Sirtuins是组蛋白和许多转录因子的赖氨酸脱乙酰基酶。最近的报告表明，SIRT1在维持ES和IPS细胞的分化中的重要性。然而，关于nampt和sirtuins在IPS细胞的造血和骨髓分化中的作用知之甚少。该项目的目的是在体外描述NAMPT-NAD+ - 苏瓜蛋白途径在人IPS细胞的造血分化中的作用，包括造血的早期和髓样细胞分化过程以及Zebrafish模型中的体内。