Administrative Core

项目总结/摘要 行政核心的主要作用是协调4个项目地点之间的研究活动， Genomics Core.生物学研究已经远远超出了对单个基因或途径的分析。 因此，该计划旨在使用全基因组分析来深入了解T细胞中差异的方式， 细胞受体（TCR）信号强度指导胸腺祖细胞采用γδ命运，以及它们如何 影响效应子命运规格。为了做到这一点，我们采用了基因组分析，最初集中在细胞 E盒DNA结合蛋白（E蛋白）的靶点，调节αβ发育中的关键检查点， γδ T细胞。我们在上一个资助周期中对E蛋白结合位点的全基因组分析揭示了一些 关键的E蛋白靶点和协作转录因子在γδ T细胞命运的采纳中是关键的。我们 现在，我们正试图通过基因组学核心来利用这些发现来评估这些E蛋白的功能 我们的全基因组E蛋白聚焦网络中的靶点，并确定它们如何影响γδ谱系命运。 该计划整合了γδ T细胞发育和E蛋白功能的四位领导者的努力。项目1将 探索E蛋白靶点Tcf 7和长链非编码RNA（lncRNA）Gm 15417在协调γδ谱系中的作用 产生IL-17的效应物命运的承诺和采纳。项目2将评估E蛋白的作用 调控元件在控制非编码转录从TCRVδ元件所采用的先天样 NKγδT细胞和TF Egr 2，其在协调NKγδ T细胞发育中起关键作用。我们的节目 他还发现，特定的E蛋白家族成员具有特定的、非冗余的作用， γδ T细胞发育和项目3将阐明其特定作用的机制基础。项目3有 还开发了一种基于多能干细胞（PSC）的人类γδ T细胞发育模型，使我们能够 评估在动物模型中的项目发现与人类的相关性。最后，项目4将评估 一种E蛋白控制的lncRNA，ThymoD，在调节T细胞系定型中的作用，以及它的丢失如何导致T细胞系定型。 αβ命运潜能在γδ命运细胞中的消失。具体来说，项目4还将采用成像 可视化ThymoD对γδ T细胞发育过程中染色体成环动力学的影响， 基因表达的关键调节器。行政核心将通过以下方式协调这些活动： 建立管理结构; 2）促进试剂的分配; 3）协调科学 项目地点之间的交流和实习生访问基因组学核心，以及必要时的其他计划 Laboratories.总的来说，我们的计划不仅有望揭示对分子控制的新见解， γδ T细胞的发展，但也将配备一个新的骨干科学家的技能，应用综合湿工作台 和生物信息学方法来解决生物学中的重要问题。

PROJECT SUMMARY/ABSTRACT The primary role of the Administrative Core is to coordinate research activities among the 4 Project Sites and Genomics Core. Biological research has moved well beyond the analysis of single genes or pathways. Accordingly, this program seeks to use genome-wide analysis to gain insight into the way that differences in T cell receptor (TCR) signal strength direct thymic progenitors to adopt the γδ fate, as well as how they might influence effector fate specification. To do so, we have employed genomic analysis focused initially on the cellular targets of E box DNA-binding proteins (E proteins), which regulate critical checkpoints in development of αβ and γδ T cells. Our genome-wide analysis of E protein binding sites in the last funding cycle revealed a number of critical E protein targets and cooperating transcription factors that are critical in adoption of the γδ T cell fate. We now seek to leverage those findings through the Genomics Core to assess the function of those E protein targets within our genome-wide E protein focused network and determine how they influence γδ lineage fate. The program integrates the efforts of four leaders in γδ T cell development and E protein function. Project 1 will explore the E protein targets, Tcf7 and long noncoding RNA (lncRNA) Gm15417, in orchestrating γδ lineage commitment and adoption of the IL-17 producing effector fate. Project 2 will assess the role of E protein regulated elements in controlling noncoding transcription from the TCRVδ element employed by innate-like NKγδT cells and the TF Egr2, which plays a critical role in orchestrating NKγδ T cell development. Our program has also discovered that particular E protein family members have specific, non-redundant roles in supporting γδ T cell development and Project 3 will elucidate the mechanistic basis for their specific roles. Project 3 has also developed a pluripotent stem cell (PSC)-based human γδ T cell development model that will enable us to assess the human relevance of program findings made in animal models. Finally, Project 4 will evaluate the role of an E protein controlled lncRNA, ThymoD, in regulating T lineage commitment and how its loss results in the extinguishing of αβ fate potential in cells committed to the γδ fate. Specifically, Project 4 will also employ imaging to visualize the effect of ThymoD on the kinetics of chromosome looping during γδ T cell development, which is a critical regulator of gene expression. The Administrative Core will coordinate these activities by: 1) re- establishing a management structure; 2) facilitating the distribution of reagents; and 3) coordinating scientific interchanges between project sites and trainee visits to the Genomics Core, and as necessary other Program Laboratories. Collectively, our program promises not only to reveal novel insights into the molecular control of γδ T cell development, but will also equip a new cadre of scientists with the skills to apply integrated wet bench and bioinformatic approaches to important questions in biology.