The research aims utilize two recently developed transgenic mouse models to study regulatory events in early T lymphocyte lineage commitment and development. Mice deficient in antigen receptor gene rearranging activity due to disruption of the RAG-2 gene show developmental arrest of early thymocytes, which can be rescued by introduction of a transgenic T cell receptor beta chain. Using these genetically defined signals for a block and progression of differentiation, genes specific for each of these developmental stages will be sought using the technique of subtractive hybridization. further characterization of these genes will be performed using targeted disruption in ES cells and chimeric reconstitution of RAG-2 deficient mice. this research has potentially important implications for the understanding of hematologic and immunodeficiency diseases, including AIDS, and the genesis of lymphoid malignancies, as well as biologic therapies such as bone marrow transplantation and gene therapy.
