The primary role of the Administrative Core is to coordinate research activities among the 4 Project Sites and Genomics Core. Biological research is moving beyond the analysis of single genes or pathways. Accordingly, this program seeks to iise genome-wide analysis to gain insight into the way that differences in T cell receptor (TCR) signal strength direct thymic progenitors to adopt the ?? fate and select an effector function. To do so, we will employ genomic analysis focused on the cellular targets of E box DNA-binding proteins (E proteins), which regulate critical checkpoints in development of ?? and ?? T cells. Genomic analysis of E protein binding sites will be coupled with novel bioinformatic tools to identify cooperating DNA-binding proteins and assemble this information into global regulatory networks defining key milestones in ?? development. The program integrates the efforts of four leaders in ?? T cell development and E protein function. Project 1 will explore the role of ligands in enabling different ?? TCR complexes to promote the adoption of distinct developmental fates. Project 2 will assess the interplay between E proteins and their Id family antagonists in regulating fate choices through actions prior to TCR expression. Project 3 will evaluate the cooperation of extracellular cues (TCR, Notch and cytokines) in, specifying ?? effector fate. Finally, Project 4 will establish comprehensive networks defining distinctions between ?? and ?? lineage commitment and their dependence on Id antagonists. These networks will serve as a framework within which the networks generated in Projects 1-3 will be interpreted. Network construction for all projects will be performed at the Genomics Core, which will also serve to instruct trainees from each program in genomic analysis. The Administrative Core will coordinate these activities by: 1) 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. Collectively, our program promises not only to reveal novel insights into the molecular control of ?? 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.
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