Biological Activity and Structural Analysis of Secreted

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The focus of my lab is the study of secreted Frizzled-related proteins (sFRPs) and their role in regulating Wnt signaling. Particular emphasis has been placed on sFRP-1, which was independently purified and cloned in my lab. Collaborative studies with recombinant sFRP-1 indicate that it can block osteoclast formation, disrupt stereocilia orientation in developing cochlea and increase intraocular pressure. A mouse model with targeted disruption of the sfrp1 gene has been created to explore the role of sFRP-1 in normal development and disease processes. We have broadened the investigation of Wnt regulation to include members of the Dickkopf family, proteins reported to specifically block the Wnt canonical/beta-catenin pathway. The differential effects of recombinant sFRPs and Dickkopfs should distinguish between the participation of canonical and non-canonical pathways in Wnt-dependent, biological responses. This approach has been used in a collaborative study to demonstrate the role of a non-canonical pathway in the response of multiple myeloma cells to Wnt stimulation. Another collaborative investigation strongly suggested that elevated levels of beta-catenin protein contributes to the neoplastic process in hematopoietic tumor cells. Prior to my sFRP/Wnt studies, my research involved keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF). Recent collaborative work has revealed a role for KGF/KGFR signaling in thymus development and T cell maturation.