Cytokines and their receptors play critical roles in intercellular communication within and between various organ systems. They have been studied extensively as growth and differentiation factors that regulate the immune system, and their actions are thought to contribute both to normal immune function and to the pathogenesis of a variety of diseases affecting the musculoskeletal system, including autoimmune syndromes and osteoporosis. Investigation of these processes typically has been undertaken either at the intracellular level (i.e., analysis of molecular pathways of signal transduction, such as the JAK-STAT cascade that regulates transcription) or at the organismal level (e.g., gene knockouts of cytokines, receptors or STAT factors), but relatively few combined approaches have been undertaken that integrate our understanding of these molecular and physiologic dimensions. The present proposal seeks to build upon extensive preliminary work within our laboratory to develop a transgenic system of analysis of cytokine/cytokine receptor actions in vivo based upon a solid understanding of the signal transduction properties of such receptors; it is expected that this model will be useful for investigation specific normal and abnormal processes within the musculoskeletal system that depend upon the actions of cytokines. This model involves a novel technology that merges two components: (1) a """"""""reporter"""""""" or """"""""indicator"""""""" system based upon cytokine-response genetic constructs introduced as transgenes into mice; and (2) a regulatable gene expression system that can be controlled temporally by pharmacologic manipulation with exogenous tetracycline. This two-component transgenic system will provide a means either for monitoring in vivo expression of a benign reporter molecule (as an indicator of cytokine receptor activation in specific tissue contexts or physiologic conditions) or for directing the specific, in vivo ablation of cells that are undergoing cytokine receptor activation (to modulate normal or disease-specific processes). Although such a system presumably will have broad applicability to a variety of scientific questions involving cytokine-dependent events, the present proposal seeks to establish proof-of-principle specifically within the limited context of processes involving the transcription factor STAT- 3, which is known to be linked to the receptor for interleukin-6 (IL-6). Studies within the scope of this pilot project will thus focus upon the acute phase response and the development of osteoporosis, both of which have been linked to this set of signaling components.
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