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. It also is being used to investigate the mechanism(s) of Wnt-dependent cell motility in an in vitro model system. Prior to the sFRP/Wnt studies, my research involved keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF). A recent collaborative study revealed a role for KGF/KGFR signaling in thymus development and T cell maturation. Several years ago Amgen, Inc. licensed patent rights to KGF for the development of therapeutic applications. A phase 3 clinical trial was completed in which KGF was shown to be safe and effective in reducing the duration and incidence of severe oral mucositis in patients with hematologic malignancies who received high dose chemotherapy and radiation prior to autologous peripheral blood progenitor cell transplantation.