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This is a first submission of an R29 submitted by a young investigator interested in the role of Lck in mature lymphocyte function. The investigator notes that protein tyrosine kinase activity is critically important for the development and function of T-cells. However, although several specific tyrosine kinases have been implicated as being functionally important, the precise roles of these individual kinases remains controversial. The investigator hypothesizes that p56ck and p59fyn carry out discreet functions and also are able to provide some overlapping and redundant activities. In this application, four specific aims are presented to identify unique functions of these kinases. The first aim is to use a thymocyte-specific lck transgene to restore T-cell development in lck-deficient mice. The investigator notes that previous work in lck-deficient mice has provided important information about the role of lck in thymocyte development. However, because mice which are deficient in lck expression develop very few T-cells and those few T-cells which do develop are phenotypically abnormal, use of these mice has not taught us anything about the role lck plays in mature T-cells. The investigator plans for his first specific aim to reconstitute normal T-cell development in lck-deficient mice by expressing an lck transgene in these mice using a cDNA driven by the lck proximal promoter. The investigator notes that since this promoter is active only in thymocytes, it should allow for normal development of mature T-cells which then will fail to express lck as the transgene is shut off in the periphery. The second specific aim is to determine the kinase substrates and signaling pathways which depend specifically on p59fyn or p56lck. For these studies, the investigator plans to compare signal transduction events in T lymphocytes derived from mice which are deficient in fyn expression and those mice which he will generate for specific aim 1. The third specific aim describes experiments to determine if deficiencies in lck or fyn differentially affect the function of T-cell subsets. For these experiments, the investigator plans to assess the proliferation and cytokine production in CD4+ T-cells compared to CD8+ T-cells. Experiments are designed further to examine development and function of TH1 versus TH2 subsets within the CD4 population. These experiments will also make use of the fyn knockout mice compared to the lck knockout mice reconstituted with an lck transgene driven by the proximal lck promoter. For the final specific aim, the investigator proposes to assess the role of p59fyn and p56lck in cytokine receptor signaling. He specifically plans to investigate responses to IL-2 and IL-7 in mature T-cells isolated from normal, fyn-knockout, and the proximal lck promoter transgenic mice. Overall, the investigator hopes that these studies will provide improved understanding of the overlapping and diverse functions of p56lck and p59fun.
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