Interleukin 2 (IL-2) serves as the dominant cell cycle progression factor for T lymphocytes, and it is well documented that reagents that inhibit or augment the function of IL-2 or its cellular receptor (IL-2R) have widespread clinical application. The primary goal of this proposal is to define the molecular mechanisms whereby IL-2R regulate T cell growth and differentiation.
The specific aims of this proposal are:
AIM 1 : REGULATION OF PROTEIN TYROSINE KINASE ACTIVITY BY IL-2R. The objective of this aim is to exploit novel constructs and cell lines for the refined analysis of PTK association and activation by IL-2. This will be achieved by: (1) The development and analysis of epitope tagged IL-2R subunits; (2) Identification of the regions within IL-2Rbeta and gamma subunits that regulate PTK activation; and (3) Definition of the requirements for association and recruitment of PTK to IL-2R subunits.
AIM 2 : MOLECULAR COUPLING OF IL-2R TO PTK-DEPENDENT SIGNAL TRANSDUCTION ELEMENTS. The objective of this aim is to utilize our unique panel of cell lines to evaluate the regulation of these proteins by IL-2. This will be achieved by examination of: (l) IL-2 dependent regulation of PI3K association and activity; (2) Regulation of Ras through the Shc-Grb2-mSOS and Vav cascades; and (3) IL-2 dependent activation of cyclins/cdc2 kinases and cell proliferation.
AIM 3 : FUNCTIONAL DEFECTS IN IL-2RGAMMA LINKED CYTOKINE PATHWAYS AND SOMATIC CELL GENE REPLACEMENT THERAPY. The objective of this aim is to utilize the unique cell lines and assays developed in AIMS l and 2 to directly pinpoint the consequences of XSCID gamma-chain mutants at the biochemical, cellular and developmental levels. This will be accomplished by: (l) The biological function of cytokine receptors in XSCID cells; (2) Repair of cytokine receptor function by genetic reconstitution with IL- 2Rgamma; and (3) Reconstitution of ex vivo thymocyte development using somatic cell gene replacement therapy. The results of this effort will have widespread importance in the basic fields of cell and molecular biology, and in the clinical setting. An increased understanding of the mechanism of IL-2R signal transduction offers hope for pharmacological intervention at multiple sites of IL-2 action, and thereby, more effective management of transplantation, cancer, autoimmunity and genetic immune deficiency such as X-linked severe combined immunodeficiency.
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