Principal Investigator/Program Director (Last, first, middle): Gascoigne, Nicholas R.J. 1 R01 AI073870-01A2 A novel gene/protein has been identified which is expressed predominantly during thymocyte development. A knockout mouse shows that it is required for normal thymocyte positive selection. Preliminary data indicate that it interacts with phospholipase C-gamma (PLC-gamma) and Itk, both enzymes crucial to early stages in signaling via the TCR, as well as with Ataxia telangiectasia mutated (ATM), a master regulator of cell cycle checkpoints that tests for DNA damage. This application aims to identify the function of this protein and to determine how it interacts with the signaling cascades in developing thymocytes. Changes in gene expression profiles in the knockout thymocytes before and during positive selection signaling will be identified. Potential functional regions of the protein will be identified and analyzed for their role in developing thymocytes, including a nuclear localization sequence, a site for phosphorylation by ATM, an SH3-binding site and others. The dynamics of the interaction with Itk and PLC-gamma will be investigated using FRET microscopy and fluorescence complementation. The induction of cell death or differentiation in developing T cells is crucial for avoiding autoimmunity, and for building a functional immune system. This newly discovered protein appears to regulate these processes, thus this project will uncover how this novel protein functions.
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|Fu, Guo; Casas, Javier; Rigaud, Stephanie et al. (2013) Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 504:441-5|
|Paster, Wolfgang; Brockmeyer, Claudia; Fu, Guo et al. (2013) GRB2-mediated recruitment of THEMIS to LAT is essential for thymocyte development. J Immunol 190:3749-56|
|Rybakin, Vasily; Gascoigne, Nicholas R J (2012) Negative selection assay based on stimulation of T cell receptor transgenic thymocytes with peptide-MHC tetramers. PLoS One 7:e43191|
|Gascoigne, Nicholas R J; Palmer, Ed (2011) Signaling in thymic selection. Curr Opin Immunol 23:207-12|
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