Cytokines govern cellular differentiation, survival and proliferation during the development of diverse cell types that circulate in the blood. Important examples of such cytokines emphasized within this proposal include: granulocyte colony stimulating factor (G-CSF), which stimulates production of neutrophils under basal and high-demand conditions; and interleukin-7 (IL-7), which is essential and non-redundant for the development of T- and B-lymphocytes. These proteins trigger similar biochemical effects within their respective target cells through receptors that have structural and functional similarities with one another. Much remains to be learned about signal transduction specificity by these cytokine receptors. For example: 1). What are the specific roles of individual signal transduction processes in mediating the physiologic actions of these cytokines in vivo? 2). What are the genes that are regulated specifically by signaling through such receptors, and do such genes contribute to lineage-specific hematopoiesis? The present proposal focuses on in vivo methods to obtain answers to these questions in selected systems. In particular, Aim 1 focuses specifically on certain STAT factors linked to the GCSF, IL-7 and related hematopoietic cytokine receptors for defining the biologic relevance of individual intracellular signaling pathways in genetically modified mouse models. We will test the hypothesis that certain STAT factors contribute directly to the development of several hemato-lymphoid lineages.
In Aim 2, the studies center on the role of the IL-7 receptor in normal lymphopoiesis; gene targeting is employed to test the hypothesis that specific signaling pathways linked to select domains of the IL-7 receptor drive the differentiation and expansion of T-cells and or B-cells. Studies in Aim 3 will use microarray technologies to define gene targets that distinguish signaling by the G-CSF receptor from that induced by related cytokine receptors affecting bone marrow progenitor cells. This work combining expression profiling and analysis of genetically modified mouse lines will establish whether specific contributions to myelopoiesis in vivo can be assigned to singular gene targets of this receptor. The results of these studies should provide insights into the pathogenesis of human diseases involving impaired production of specific hemato-lymphoid cell types. The findings should also point to new, rational therapeutic avenues for reversing these conditions in some settings.
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