血小板生成素（TPO）及其受体Mpl所介导的信号通路在巨核谱系造血中发挥关键作用，TPO/Mpl信号通路异常与多种造血疾病的发生密切相关。目前对于TPO/Mpl通路的调节机制还不完全清楚。人白细胞相关免疫球蛋白样受体1 (LAIR-1) 是一种以胶原为配体的免疫抑制性受体。我们最近发现，LAIR-1能够抑制TPO诱导的CD34+细胞向巨核细胞分化。本项目拟在前期工作基础上，采用慢病毒转染和shRNA干涉等方法干预CD34+细胞LAIR-1的表达，分别在体内SCID小鼠移植模型和体外成骨细胞共培养体系中研究LAIR-1在巨核系造血中的作用及其对TPO诱导的巨核谱系定向分化的影响；进而采用抗体芯片和western blot等方法研究LAIR-1 对TPO/Mpl信号通路的调节机制。本项目的研究不仅有助于揭示一种新的巨核谱系造血调控模式，还将为TPO/Mpl信号通路异常致病机理的研究提供新思路。

Thrombopoietin (TPO) and its receptor MPL initiated signaling plays a pivotal role in megakaryopoiesis. Although numerous pathologies of the megakaryocyte (MK) lineage are now explained by molecular abnormalities in the activity of TPO/MPL signals, as well as in signaling molecules associated with MPL, the mechanisms through which TPO/Mpl signal pathways be regulated are not well understood. ..Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor which belongs to the immune inhibitory receptor family. Our recent findings show that LAIR-1 serves as a negative regulator in TPO-mediated differentiation of MK. To extend our understanding of normal and pathologic megakaryopoiesis, in this work we design to using lentiviral expression system and shRNA knockdown strategy to intervene the expressing of LAIR-1 on human cord blood CD34+ cells firstly. Thereafter, an in vivo NOD/SCID transplantion model and an in vitro osteoblast co-culture system will be employed to further investigate the role of LAIR-1 in regulation of megakaryopoiesis and TPO-induced commitment of hematopoietic progenitors to the MK lineage respectively. On this basis, we will further investigate the mechanism of LAIR-1 in regulation of TPO/Mpl signal pathways by antibody microarray and western blot. ..Therefore, these experiments may help to illustrate a novel regulatory mechanism of megakaryopoiesis and provide new insights into the understanding of molecular pathogenesis of megakaryocytic lineage-related disorders.