Regulation of Wnt Signaling in Development

发育过程中 Wnt 信号传导的调控

• 批准号: RGPIN-2016-06207
• 负责人: VanRaay, Terence
• 金额: $ 2.04万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630500
• 关键词: Regulation; Wnt; Signaling; Development

Progressing from a single fertilized cell into a mature organism requires immeasurable coordination of multiple signaling pathways acting in concert. Part of this coordination comes from communication between different signaling pathways and part comes from communication within a signaling pathway, the so-called intrinsic feedback mechanisms. My long-term goals are to understand how these intrinsic feedback mechanisms work to control signaling pathways that, in turn, control development. My short-term goals are to understand the molecular function of how negative feedback regulators control the Wnt pathway. The Wnt pathway is critically important for both early development and in the maintenance of stem cells in the adult. Our investigations will utilize traditional cell culture but also take advantage of the early zebrafish embryo because of its optical transparency, genetics and evolutionary conserved mechanisms. Further, this model provides a native environment in which to investigate the Wnt pathway, which will contribute to our universal understanding of its intrinsic regulation. In this proposal, we will investigate two negative feedback regulators: Nkd1 and Axin2. In Aim 1 we will determine how Nkd1 and Axin2 control the intensity and duration of the Wnt signal during early zebrafish development. We will use state-of-the-art genetic engineering tools to knockout Nkd1 and Axin2 function and observe how these mutants respond to perturbed Wnt signaling.

从单个受精细胞发展成成熟生物体需要多个信号通路的不可估量的协调一致作用。这种协调部分来自不同信号通路之间的通信，部分来自信号通路内的通信，即所谓的内在反馈机制。我的长期目标是了解这些内在反馈机制如何控制信号通路，进而控制发育。我的短期目标是了解负反馈调节器如何控制 Wnt 通路的分子功能。 Wnt 通路对于成人干细胞的早期发育和维持都至关重要。我们的研究将利用传统的细胞培养，但也会利用早期斑马鱼胚胎，因为它的光学透明性、遗传学和进化保守机制。此外，该模型提供了研究 Wnt 通路的原生环境，这将有助于我们对其内在调控的普遍理解。在本提案中，我们将研究两个负反馈调节因子：Nkd1 和 Axin2。在目标 1 中，我们将确定 Nkd1 和 Axin2 在早期斑马鱼发育过程中如何控制 Wnt 信号的强度和持续时间。我们将使用最先进的基因工程工具来敲除 Nkd1 和 Axin2 功能，并观察这些突变体如何响应扰动的 Wnt 信号传导。