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.

诱导多能干 (iPS) 细胞是具有胚胎干 (ES) 细胞样特征的重编程体细胞，通过将特定转录因子（Oct 3/4、Sox2、Klf4，有或没有 c-MYC）引入部分或完全分化的体细胞（例如成纤维细胞、CD34+ 骨髓造血细胞、来自人类的角质形成细胞）而产生。 头发）。使用 iPS 细胞模型的研究有助于阐明几种造血谱系的谱系规范和分化过程。我们最近报道烟酰胺磷酸核糖转移酶（NAMPT）-NAD+-SIRT1通路在体外和体内G-CSF诱导CD34+造血细胞的骨髓分化中发挥重要作用。 NAMPT 是一种限速酶，可将烟酰胺转化为 NAD+ 并激活 NAD+ 依赖性蛋白脱乙酰酶 Sirtuins。 Sirtuins 是众所周知的组蛋白和多种转录因子的赖氨酸脱乙酰酶。最近的报告证明了 SIRT1 在维持 ES 和 iPS 细胞的多能性和分化中的重要性。然而，人们对 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和斑马鱼模型中描述 NAMPT-NAD+-Sirtuins 通路在人类 iPS 细胞造血分化（包括早期造血和骨髓细胞分化过程）中的作用。