从体外获得有功能的造血干细胞是基础科学和再生医学关注的焦点。解决此问题的瓶颈就在于人们对造血干细胞的产生、维持和分化的机制知之甚少。申请人围绕“造血干细胞发育分化及其微环境”这一科学问题，通过细胞生物学和分子生物学等多种研究手段，以遗传与表观遗传调控因子为切入点，从多角度、多层次系统阐释造血干细胞发育的调控网络，取得了一系列原创性成果。在造血干细胞命运决定和产生过程中，BMP和ERK信号通路形成的调控网络（Nat Commun，2014）、ETS转录因子Fev（Blood, 2013）和miR-142-3p（Cell Res, 2013）起关键作用。在造血干细胞的维持阶段，微环境中血液流动的调控是必需的（Blood, 2011）。此外，还揭示了在造血干细胞向T细胞分化的过程中Foxn1的分子调控机制（PNAS, 2012）。这些发现为体外扩增造血干细胞并应用于转化医学奠定了理论基础。

To obtain functional hematopoietic stem cells (HSCs) in vitro is a major goal of basic research in hematopoiesis and holds great promise in regenerative medicine. However, production of transplantable HSCs in vitro has not yet been achieved. The bottleneck for this is that the molecular mechanisms of HSC development (emergence, maintenance and differentiation) in vivo are still poorly understood. Using zebrafish as a model and multiple approaches, the applicant has made a series of accomplishments on ‘hematopoietic stem cell development, differentiation and microenvironment’ in the past five years, including: 1) Inhibition of ERK signaling by BMP-SMAD1/5 is essential for hemogenic endothelium-derived HSC emergence (Nat Commun，2014); 2) Fev regulates HSC development via ERK signaling (Blood, 2013); 3) Mir142-3p regulates the formation and differentiation of HSCs in vertebrates (Cell Res, 2013); 4) Blood flow is essential for the maintenance of HSC development through KLF-NO signaling cascade (Blood, 2011); 5) Foxn1 regulates thymus and T cell development via direct regulation of mcm2 (PNAS, 2012). These findings expand our understanding on the gene regulatory network of HSC development in vertebrates, and the cell intrinsic and extrinsic regulation of HSC programming by genetic and epigenetic factors, and will provide new insights into the in vitro generation of transplantable HSCs for potential clinical applications.

脂类代谢调控包括脂质吸收、合成、储积和脂类运输等多个调控过程。虽然研究已经发现SREBP, PPAR, C/EBP等多个脂质合成和脂肪细胞发育分化的调控因子，但脂质储积的调控机制及脂质储积调控在个体发育中的作用有待阐明，多个关键问题有待解决。我们利用在体系统，大规模地挖掘脂质储积调控因子。通过对这些因子的功能分析和调控的通路分析，我们系统性地研究脂质储积调控及其相关组织细胞生长发育的分子机制。我们发现胞嘧啶二脂酰甘油合成酶CdsA通过胰岛素（Insulin）信号通路协同调控细胞生长发育和脂类储积。该合成酶能够将磷脂酸（PA）从合成甘油三酯转到合成磷脂酰肌醇（PI），从而行使分子开关的功能，调控脂类存贮过程向细胞生长发育过程的转化。此外，在对一个脂营养不良疾病BSCL2的果蝇模型研究中发现，Seipin通过调控细胞内钙离子动态平衡促进脂肪存储的分子功能，恢复内质网内的钙水平可以很好的挽救dSeipin突变导致的脂肪存储缺陷。从而建立了胞内钙离子动态平衡与脂肪存储之间的联系，为脂肪缺乏症病人提供了一种潜在的治疗手段。