Administrative Core

Research Inst Of Fox Chase Can Ctr, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY/ABSTRACT - ADMINISTRATIVE CORE The primary role of the Administrative Core is to coordinate research activities among the 4 Projects (5 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, single cell analysis to gain insight into the way that differences in T cell receptor (TCR) signal strength direct thymic progenitors to adopt the  fate and how the molecular and genomic alterations occurring during specification in mice align with those in human  development. To do so, we have employed genomic analysis focused initially on the genomic targets of E box DNA-binding proteins (E proteins), which regulate critical checkpoints in development of  and  T cells. Our genome-wide analysis of E protein binding sites in the last funding cycle led to the identification of targets and cooperating transcription factors through which E proteins control  lineage fate in mouse and now serves as a foundation from which we will build a richer, more comprehensive understanding of this process and how it aligns with the equivalent developmental branchpoints navigated by human  T cell progenitors. In doing so, we will leverage an outstanding Genomics Core to both identify the regulatory elements through which  lineage and function are controlled and assess their activity at a genome wide scale. The program integrates the efforts of six leaders in  T cell development and E protein function. Project 1 will explore the role of E protein- TCF1 cooperation in  fate specification, since TCF1 is both a direct E protein target and a critical cooperating transcription factor through which E proteins regulate fate. Project 2 integrates the expertise of two leaders in genomics and in structural analysis of TCR-ligand interactions to elucidate the role of TCR signal strength in specification of human  T cells and how molecular and genomic events accompanying specification align with equivalent events in mice. Our program has also discovered that particular E protein family members play unique roles in supporting  T cell development and Project 3 will elucidate the mechanistic basis for their specific actions. Project 3 also made the paradigm-shifting observation that, contrary to the prevailing view in the field, development of some  T cells is regulated by recognition of major histocompatibility complex class I-peptide ligands. Finally, Project 4 developed a method for imaging in real time in living cells, the transcriptional dynamics of the central regulator of E protein function, E protein antagonist Id3. Project 4 determined that Id3 transcription occurs in bursts, and now seeks to understand how the bursts are affected by TCR strength and the subnuclear location in which they are occurring. 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 the Genomics Core. Collectively, our program promises to both reveal novel insights into the molecular control of  T cell development and equip a new cadre of scientists with the skills to apply integrated wet bench and bioinformatic approaches to important questions in biology.