Research objectives and content
It is known that a variety of cytokines is involved in Iymphocyte development and differentiation, and that defects in the common cytokine receptor y chain utilized by IL-2, IL-4, IL-7, IL-9 and IL-15 results in abnormal Iymphoid development. Three major pathways have been identified following IL-2 binding to IL-2 receptor: l)the induction of proto-oncogenes c-fos and c-jun following pS61ck, 2)c-myc induction due to syk kinase activation, and 3)a pathway that increases bcl-2 levels. This project will attempt to identify the role of some of these signaling pathways to Iymphoid development, using theyc-deficient (y = gamma) mouse model, in vivo and in vitro. c-deficient hematopoietic precursors purified by cell sorting techniques will be transfered using retroviral infection with yc cDNA constructs. The modified precursor cells will be then placed either in defined in vitro culture conditions which flavor Iymphoid development or will be used to graft yc-deficient mice (in an attempt to reconstitute the Iymphoid system in vivo. Since yc cells fail to activate any of the above mentioned signaling cascade, by transducing yc chimeric cDNA molecules which can only associate or activate individual signaling pathways, we hope to define the roles of these various pathways for biologically relevant phenomena, in this case, Iymphoid
differentiation.Training content (objective, benefit and expected impact)
Our project will try to elucidate the yc receptor signaling pathways in the development of the cells which belong to the Iymphoid lineage, using the yc knockout mice and retroviral infection techniques. The applicant will acquire knowledge in the fields of biochemistry, cellular and molecular immunology.
Links with industry / industrial relevance (22)
The project is directly linked with the medical research because of the importance of the receptor yc in the human X-linked severe combined immunodeficiency(SCIDX1). Potential gene therapy techniques can revolutionise the treatment.