MURINE MODELS OF THE WISKOTT ALDRICH SYNDROME

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The Wiskott-Aldrich syndrome (WAS) is a hematological disorder characterized by a T-and B-cell immunodeficiency, eczema, and thrombocytopenia. The defective protein (WASP) is thought to play a critical role in a complex signaling pathway in hematopoietic cells that involves the coordination of cell surface signals and cytoskeletal structural changes. Recently, we have disrupted the WAS gene in murine embryonic stem (ES) cells and used the RAG2-deficient blastocyst complementation system to show that WASP-deficient murine lymphocytes have proliferation defects that closely resemble the defects in WAS patients. In addition, we have identified several cellular signaling molecules, including Cdc42, that interact with WASP. Finally, we have identified th human and murine homologues of the second WASP-family member (N-WASP. This project seeks to build on these studies to establish a murine model for the WAS and to further elucidate the function of WASP and WASP-related proteins. Our first aim is to characterize defects of the function of WASP and WASP-related proteins. Our first aim is to characterize defects of the immune system in WASP-deficient mice. Our second goal is to evaluate N-WASP function by gene targeted mutational and genetic comlementation approaches. The third goal is to employ human WASP- deficient platelets and WASP-deficient mice to study the role of WASP in platelet production and function. Our final goal is to elucidate functional domains of WASP and N-WASP by genetic complementation approaches. These studies should provide further insight into the pathogenesis associated with WAS while providing more general insights into the role of WASP-family proteins in intracellular signaling pathways that control cytoskeletal reorganization.