申请人主要从事造血干细胞（HSC）和T细胞维系与发育的研究。已取得成果包括:1)阐明GABP四聚体通过细胞周期和凋亡通路，特异调节HSC和肿瘤干细胞(LSC)的维系和扩展。2)首次发现Wnt信号通路下游转录因子TCF1是重要的抑癌因子，能直接结合并抑制LEF1的过量表达来抑制肿瘤。3)发现TCF1通过效应基因Eomes调控记忆性CD8T细胞。发表SCI论文20篇，第一作者文章（10篇）累计影响因子超过100；以第一作者身份在权威杂志上发表5篇文章，包括Cell Stem cell (2012)，Immunity（2010，2012），Blood（2011，2013）。两项发表于Immunity杂志的成果都被Faculty1000收录。进一步工作将以TCF1/LEF1双敲除小鼠为模型研究Wnt信号通路在HSC和LSC中的重要功能，以期深入理解血液疾病的发生机理并为临床诊断治疗提供新的切入点。

The candidate’s research interests focus on hematopoietic stem cells (HSCs) and early stage T-cell development. His major achievements include: 1) GABP factors control the network of regulating HSC through cell cycle and apoptosis, and the GABPα2β2 tetramer is specifically required for self-renewal of HSCs and leukemic stem cells (LSCs) in a chronic myelogenous leukemia (CML) model; 2) TCF-1, one of the downstream transcription factors of canonical Wnt signaling, as a tumor suppresser gene and restrains LEF-1 expression to suppress T-cell malignancy; 3) TCF-1 as a key player that regulates both primary and secondary effector CD8 T cells and memory CD8 T cell, and Wnt-TCF-1 pathway acts upstream of eomesodermin (Eomes) in memory CD8+ T cells for their differentiation and longevity. The candidate’s accomplishments in this scientific field are well reflected in his strong publication record. To date, he has published 20 papers in authoritative journals indexed by SCINCE CITATION INDEX (SCI), and 10 out of 20 are first author or co-first-author papers published in high profile journals (total Impact factor over 100). These very prestigious publications include one in Cell Stem Cell (2012), two in Immunity (2010 & 2012) and two in Blood (2011 & 2013). Moreover, two of his papers published in Immunity were highlighted and accompanied by Preview articles by authoritative experts, and these articles have also been highly recommended by Faculty of 1000 with a “Must Read” rating. To further clarify the function of canonical Wnt signaling pathway in HSCs and LSCs, the TCF-1 and LEF-1 double deficiency mice model were generated and will be analyzed by molecular and cellular experimental approaches. The involved studies will not only provide significant new insights into the roles of TCF-1and LEF-1 in modulating canonical Wnt signaling in HSCs and LSCs , but also will have implications for clinical stem cell biology and the development of new drugs.

血液干细胞（HSC）的发育和分化受到多种信号通路的调控，经典Wnt信号通路在HSC分化和自我更新中的功能一直是领域内的研究热点。本项目资助期间，主要研究方向是经典Wnt信号通路下游的两个重要转录因子TCF1和LEF1在HSC中的功能和调控机制分析。以双缺失小鼠（Vavi-creTCF1-/-LEF1fl/fl）为模式动物，通过系统的实验阐明了Wnt信号通路下游转录因子TCF1/LEF1通过调控HSC的细胞周期，从而调控HSC自我更新以及分化发育。利用TCF1/LEF1双缺失小鼠制备慢性粒细胞白血病（CML）的小鼠模型，证明TCF1/LEF1对肿瘤干细胞（LSC）的维系和扩展具有重要功能，机制研究发现这种调控是通过下游靶基因Egr1实现的。此部分研究结果发表在2016年的JBC杂志上；资助期间的相关研究也已发表多篇SCI研究论文，其中3篇标注为本项目资助。深入分析经典Wnt信号通路下游转录因子TCF1/LEF1在HSC和LSC中的重要功能，为临床应用基因和药物联合治疗提供了新的线索。在本项目的资助期间，还有相关重要的发现如下：1）发现wnt信号通路的辅因子LRP5、LRP6的缺失通过调控细胞周期对HSC的分化发育有着重要的作用。2）发现HSC向着淋巴细胞发育的过程中，GABP四聚体对HSC到NK细胞的发育有着重要的调控作用。3）Tmco1作为一个钙调节蛋白对HSC重建过程中对淋巴细胞的发育也有着重要的作用，缺失Tmco1造成HSC重建T、B、NK等淋巴细胞的能力显著降低，相关研究正在深入进行，也将是本课题组今后的研究重点之一。本项目的顺利完成，为深入理解HSC的维系分化和HSC向着淋巴细胞系发育的相关机制提供了新的理论支撑和多个的潜在研究方向。