This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. T cell-mediated immunity against viral pathogenesis is dependent on the successful transduction of signals from the TCR and CD28 into the cell. The TCR complex contains the antigen recognition and signaling motifs. The CD28 co-receptor delivers a critical second signal, without which the cell would become anergic and undergo apoptosis. The second signal ensures that the antigenic stimulation of the TCR occurs in the appropriate immune context. The goal of this research project is to examine the CD28-mediated signals that are required for T cell activation. Evidence from our laboratory and others suggest that CD28 and the Gads adaptor protein regulate survival and proliferation through the Akt serine/threonine kinase. We hypothesize that Gads, CD28, and Akt are linked in a common signaling pathway that is required for normal T cell development and activation. To test this hypothesis, we will focus on threee specific aims.
Specific aim 1 describes the use of Gads-deficient mice to examine CD28-mediated Akt phosphorylation.
Specific aim 2 will test the hypothesis that a quaternary signaling complex links CD28, Gads, PI3-K, and c-Cbl that may lead to enhanced Akt phosphorylation. Biochemical experiments examing this putative mutlimeric complex are described. Finally, experiments described in specific aim 3 apply genetic techniques to examine the link between CD28 and Gads. T cell development in Gads-deficient, CD28-deficient, and Gads/CD28 double deficient mice will be analyzed. In summary, the experiments detailed in this proposal will examine the signaling pathway that links CD28, Gads, PI3-K, and c-Cbl.
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