Biological Activity and Structural Analysis of Secreted

分泌物的生物活性及结构分析

• 批准号: 7049738
• 负责人: JEFFREY RUBIN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7049738
• 关键词: biological signal transduction; cadherins; developmental genetics; gene expression; gene targeting; genetic models; genetically modified animals; laboratory mouse; model design /development; pathologic process; protein protein interaction; protein structure function; proteins; recombinant proteins

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.

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。已经建立了一种靶向破坏Sfrp 1基因的小鼠模型，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。它也被用于研究体外模型系统中Wnt依赖性细胞运动的机制。 在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，Amgen，Inc.获得KGF的专利权，用于开发治疗应用。完成了一项3期临床试验，在该试验中，KGF被证明在自体外周血祖细胞移植前接受高剂量化疗和放疗的恶性血液病患者中，在减少严重口腔粘膜炎的持续时间和发生率方面是安全有效的。