Recent advances in biomedical science have made it possible to perform cell-based genetic screens inmammalian cells to uncover gene-specific functions in a high throughput fashion. These include thesequencing of the human and mouse genomes, the assembly of non-redundant genome-wide collections ofcDNAs, the development of RNA interference methods in mammalian cells, and the assembly of genomewidecollections of short hairpin RNAs (shRNAs) that can target known genes. The overall goal of theGenomic Resources Core is to facilitate the application of these advances in four projects of the Program, tomake it possible to interrogate gene function during T cell receptor (TCR) engagement.and subsequentsignaling. The Genomic Resources Core will grant investigators in the program access to cDNA and shRNAlibraries that have genomic coverage and which are stored and maintained in the Johns Hopkins HighThroughput Biology (HiT) Center. Using facilities in the Pomerantz laboratory, the Genomic Resources Corewill provide a centralized facility for processing the bacterial aliquots provided by the HiT Center, including A)preparation of DNA from the bacterial aliquots for transient transfection; B) packaging of shRNA-expressingviral constructs into virus for infection of target cells; C) infection of target cells with packaged virus; D) thetransfer of library clone cDNA inserts into appropriate expression vectors for screening; and E) pooling oflibrary clones to maximize the number of genes to be screened per assay. The Genomic Resources Corewill allow for unbiased screens for genes that play a role in TCR engagement and signaling, as well as fortargeted study of candidate genes that are hypothesized to play critical roles in these processes. Project 1will use the Core to identify genes involved in TCR clustering during activation. Project 3 will use the Core totest the role of candidate genes involved in the Sproutyl -mediated regulation of TCR signaling. Project 4 willuse the Core to survey tyrosine kinase genes for potential roles in TCR-induced calcium signaling. Project 5will use the Core to identify modulators of TCR signaling to NF-KB. Since inappropriate TCR signaling canresult in ineffective immune surveillance, autoimmunity, or cancer, the results of these screening efforts mayprovide molecular targets for new therapies designed to treat diseases of the immune system.
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