Activity & Structural Analysis of Secreted Proteins

我的实验室的重点是研究分泌型FrizzledRelated Proteins(SFRP)及其在调节Wnt信号中的作用。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，它可以阻止破骨细胞的形成，扰乱耳蜗发育中的立体纤毛定向，并提高眼压。为了探索SFRP-1在正常发育和疾病过程中的作用，已经建立了一个靶向破坏SFRP1基因的小鼠模型。我们扩大了对Wnt调控的研究，包括Dickkopf家族的成员，据报道，Dickkopf家族的蛋白质特异性地阻断Wnt正则/β-连环蛋白途径。重组sFRPs和Dickkopf的不同效应应该区分参与Wnt依赖的生物反应的规范和非规范途径。这一方法已经被用于一项合作研究，以证明非规范途径在多发性骨髓瘤细胞对Wnt刺激的反应中的作用。它也被用来在体外模型系统中研究依赖WNT的细胞运动的机制(S)。 在SFRP/WNT研究之前，我的研究涉及角质形成细胞生长因子(KGF)和肝细胞生长因子(HGF)。最近的一项合作研究揭示了KGF/KGFR信号在胸腺发育和T细胞成熟中的作用。几年前，安进公司向KGF授予了用于治疗应用开发的专利权。今年完成了一项第三阶段临床试验，在这项试验中，KGF被证明是安全和有效的，可以减少血液肿瘤患者在自体外周血祖细胞移植之前接受高剂量化疗和放射治疗的严重口腔粘膜炎的持续时间和发生率。

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. This year 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.