巨核细胞是产生血小板的前体细胞，其过度发育分化导致炎症性和原发性血小板增多症。炎症反应因子STAT1促进巨核细胞发育分化，其信号转导在JAK2突变阳性的原发性血小板增多症中显著活化，可能是导致血小板增多症的重要因素。本课题提出研究STAT1调控巨核细胞发育分化的分子机制，鉴定STAT1靶基因并探讨其在巨核细胞发育分化中的功能和作用机理。首先，利用STAT1缺失小鼠进行骨髓移植，探讨其在原发性血小板增多症发生中的功能。其次，利用巨核细胞体外分化的模型鉴定STAT1靶基因，并验证部分靶基因在体内/体外巨核细胞发育分化和血小板形成中的功能。最后，我们将剖析STAT1通过调控TMCC2、RUNX1、NFE2等基因促进巨核细胞发育分化的分子机制，构建包括信号转导、转录调控、蛋白相互作用等方面的分子调控网络。该课题研究的实施，将全面阐释炎症性和原发性血小板增多症的发病机制，为临床干预提供科学的依据。

Megakaryocytes are platelet-producing cells. Excessive proliferation, development, and differentiation of megakaryocytes lead to inflammatory or essential thrombocythemia. STAT1, one major inflammatiory factor, has been shown to promote development and differentiation of megakaryocytes and its signaling is significantly activated in blood cells from essential thrombocythemia patients with JAK2 mutation. Thus we hypothesize that STAT1 signaling is the major player mediating thrombocythemia under pathological conditions. We propose to identify STAT1 target genes in megakaryocytes and study how these genes are regulated by STAT1, what functions they play in megakaryocyte development and differentiation, and the molecular mechansims by which they exert their functions. First, we will probe how STAT1 affects the pathogenesis of essential thrombocythemia using bone marrow transplation. Second, we will identify STAT1 target genes by using G1ME and K562, two megakaryocyte differentiation cell models. And verify their functions of several interesting genes in megakaryopoiesis/thrombopoeisis in vitro and in vivo. Finally, we will dissect the molecular mechanisms by which STAT1 promotes megakaryocyte development and differentiation through regulating TMCC2, RUNX1, and NFE2 genes. And build the molecular regulation network including signal transduction, transcriptional regulation, protein-protein interaction. Once the proposal is carried out, we will be able to fully interpret the pathegenetic mechanism of inflammatory and essential thrombocythemia and provide scientific evidence for clinic interference.