Dynamics of Wnt receptor activation, signal initiation and signal termination in vivo

体内 Wnt 受体激活、信号起始和信号终止的动力学

• 批准号: 1353799
• 负责人: Marcel Wehrli
• 金额: $ 60万
• 依托单位: Oregon Health & Science University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1353799&HistoricalAwards=false
• 关键词: Dynamics; Wnt; receptor; activation; signal

NSF Proposal IOS-1353799Marcel Wehrli, Ph.D.Dynamics of Wnt receptor activation, signal initiation and signal termination in vivoCells of developing embryos and adult tissues must receive and precisely interpret specific signals for proper growth. Secreted proteins of the Wnt family represent one such signal. Wnts elicit precise changes in gene expression mediated by increased levels of the protein ?beta-catenin. Too much or too little signal leads to tissue defects and disease. While it is known that Wnts activate cell surface receptors, it remains unclear where on the cell membrane or inside the cell the ligand-activated receptor functions, how it activates the intracellular signaling cascade via the protein Dishevelled and how the receptor is turned off. This proposal addresses these questions directly with a novel in vivo approach. In addition, it will identify how Dishevelled blocks the central regulator in the pathway, a protein complex assembled around the scaffold protein Axin, and is expected to identify in vivo how the receptor-initiated signal leads to the inhibition of the Axin complex and induces beta-catenin signaling, a process that remains controversial. Broader ImpactOur understanding of the Wnt/beta-catenin pathway has increased dramatically in recent years. However, many findings are derived from in vitro experiments and their functional significance is limited. The signaling events of the Wnt/beta-catenin pathway are amenable to investigation in their normal cellular context using the Drosophila model system, underscoring the significance of the studies proposed here. These investigations are expected to identify dynamically changing interactions as the signal is transduced, thereby greatly increasing our understanding of this important signaling mechanism.This proposal will provide an opportunity for one graduate student and three undergraduates to engage in cutting edge research. In addition, it will allow the PI to introduce K-12 students to basic development and genetics and to promote a science-based curriculum in local schools.

NSF提案IOS-1353799 Marcel Wehrli博士，Wnt受体激活、信号启动和信号终止在体内的动力学发育中的胚胎和成体组织的细胞必须接收并精确地解释特定的信号以进行适当的生长。Wnt家族的分泌蛋白代表一种这样的信号。Wnt通过增加蛋白质水平引起基因表达的精确变化？β-连环蛋白。太多或太少的信号会导致组织缺陷和疾病。虽然已知Wnt激活细胞表面受体，但仍不清楚配体激活的受体在细胞膜上或细胞内的何处起作用，它如何通过Dishevelled蛋白激活细胞内信号级联以及受体如何关闭。该提案直接用一种新的体内方法解决了这些问题。此外，它将确定Dishevelled如何阻断通路中的中央调节因子，一种围绕支架蛋白Axin组装的蛋白质复合物，并有望在体内确定受体启动的信号如何导致Axin复合物的抑制并诱导β-连环蛋白信号传导，这一过程仍然存在争议。更广泛的影响近年来，我们对Wnt/β-catenin通路的理解急剧增加。然而，许多研究结果来自体外实验，其功能意义有限。Wnt/β-连环蛋白通路的信号事件是服从调查在其正常的细胞环境中使用果蝇模型系统，强调了这里提出的研究的意义。这些调查预计将确定动态变化的相互作用，因为信号被transduced，从而大大增加了我们对这一重要的信号机制的理解。这个建议将提供一个机会，一个研究生和三个本科生从事前沿研究。此外，它将允许PI向K-12学生介绍基本发展和遗传学，并在当地学校推广以科学为基础的课程。