Biochemistry of Leukemia Virus Core Binding Factor

摘要 这项建议的目标是了解先天免疫信号如何有助于 胚胎中的造血干细胞(HSC)。了解HSC是如何形成的，尤其是信令 参与胚胎肝星状细胞形成的途径将是生产和扩增肝星状细胞所必需的。 来自体外的其他细胞来源，这是再生医学的一个主要目标。所有成人的造血干细胞都是从 来自胚胎中的血液内皮细胞。血源性内皮分布于多个解剖部位 包括卵黄囊和主要动脉，但只有主要动脉中的血源性内皮细胞才能产生 造血干细胞。我们和其他人发现，多个先天免疫和炎症信号通路调节 在小鼠和斑马鱼胚胎的主要动脉中形成肝星状细胞。这项提案的重点是 Toll样受体(TLR)信号在胚胎HSC形成中的作用我们将决定哪一只手臂 Toll样受体信号通路，以及哪些Toll样受体调节HSC的形成，以及在哪些步骤 在这个过程中，他们采取了行动。我们还将研究在HSC形成过程中Toll样受体信号是否在 胚胎导致成年HSCs的功能、转录组和表观基因组的长期变化。

Summary The goal of this proposal is to understand how innate immune signaling contributes to the formation of hematopoietic stem cells (HSCs) in the embryo. Understanding how HSCs form, and in particular the signaling pathways that are involved in embryonic HSC formation will be essential for producing and expanding HSCs from other cell sources ex vivo, which is a major goal in regenerative medicine. All adult HSCs are derived from hemogenic endothelial cells in the embryo. Hemogenic endothelium is located in several anatomic sites including the yolk sac and the major arteries, but only hemogenic endothelium in the major arteries produces HSCs. We and others discovered that multiple innate immune and inflammatory signaling pathways regulate HSC formation in the major arteries of mouse and zebrafish embryos. This proposal focuses on the contribution of toll-like receptor (TLR) signaling to embryonic HSC formation. We will determine which arms of toll-like receptor signaling pathways, and which toll-like receptors regulate HSC formation, and at which steps in the process they act. We will also examine whether toll-like receptor signaling during HSC formation in the embryo introduces long-term alterations to the function, transcriptome, and epigenome of adult HSCs.