Biological Activity and Structural Analysis of Secreted

我的实验室的重点是研究分泌型卷曲相关蛋白（sFRPs）及其在调节Wnt信号转导中的作用。特别强调的是sFRP-1，它是在我的实验室独立纯化和克隆的。与重组sFRP-1的合作研究表明，它可以阻断破骨细胞的形成，破坏发育中耳蜗的静纤毛定向，并增加眼内压。已经建立了sfrp 1基因靶向破坏的小鼠模型，以探索sFRP-1在正常发育和疾病过程中的作用。我们已经扩大了Wnt调控的研究范围，包括Dickkopf家族的成员，这些蛋白质被报道特异性阻断Wnt经典/β-连环蛋白通路。重组sFRPs和Dickkopfs的差异效应应区分Wnt依赖性生物反应中典型和非典型途径的参与。这种方法已被用于一项合作研究，以证明非经典途径在多发性骨髓瘤细胞对Wnt刺激的反应中的作用。另一项合作研究强烈表明，β-连环蛋白水平升高有助于造血肿瘤细胞的肿瘤过程。 在我的sFRP/Wnt研究之前，我的研究涉及角质细胞生长因子（KGF）和肝细胞生长因子（HGF）。最近的合作工作揭示了KGF/KGFR信号在胸腺发育和T细胞成熟中的作用。

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.