The long term goal of this proposal is to determine the in vivo function of the tyrosine kinase receptor known as Ron. Based on in vitro analyses, Ron has been postulated to have a critical role in cellular proliferation, dissociation and migration-processes important for normal organ function and regeneration following trauma. Additionally, Ron is thought be involved in liver function and in hematopoiesis, particularly in the development of macrophage, osteoclasts and megakaryocytes as well as in many aspects of the immune response including macrophage activation, antigen presentation and nitric oxide regulation. An association with Ron in the wound healing process has also been inferred by virtue of this receptor's involvement in keratinocyte migration and proliferation. In an initial attempt to determine the function of Ron in vivo, mice were generated containing a targeted deletion of this gene. These mice however, die early during embryonic development. To circumvent the early embryonic lethality and to study the later functional significance of Ron in individual organs, a conditional knockout strategy involving the bacterial Cre/loxP recombinase system will be employed. By generating mice containing a tissue-restricted deletion of Ron in the liver, the role of this protein in the growth, development and regenerative processes of this organ will be directly accessed. Furthermore, the mice produced in these experiments will be used to examine the function of Ron in macrophage activation, inflammation and hematopoiesis. Secondly, the role of Ron in skin morphology and wound healing processes will be evaluated by producing a deletion of this receptor specifically in this organ. Finally, experiments are proposed to examine the consequences of a constitutively activated form of Ron on the normal growth and development of mice in vivo. These experiments should significantly aid in our understanding of the in vivo importance of this receptor tyrosine kinase in many of the processes outlined above.
