R01:WNT AND BETA-CATENIN SIGNALING IN REGENERATION

R01：再生中的 WNT 和 β-连环蛋白信号传导

• 批准号: 7409545
• 负责人: Randall Todd Moon
• 金额: $ 20.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409545
• 关键词: Adult; Animal Model; Biological Process; Cell Proliferation; Cells; Data; Dominant-Negative Mutation; Family; Fishes; Future; Gene Targeting; Genes; Goals; Green Fluorescent Proteins; Heart; Heat-Shock Response; Human; Implant; Ligands; Limb structure; Medicine; Monitor; Moon; Mus; Natural regeneration; Numbers; Organism; Orthologous Gene; Pathway interactions; Patients; Rana; Research; Research Personnel; Retina; Role; Role playing therapy; Signal Transduction; Signal Transduction Pathway; Spinal Cord; Spinal cord injury; Structure; Tadpoles; Testing; Therapeutic Uses; Transgenic Organisms; Vertebrates; Xenopus; Zebrafish; beta catenin; cell motility; experience; gain of function; improved; inhibitor/antagonist; injured; limb regeneration; loss of function; member; mouse model; nerve stem cell; programs; promoter; research study; response; spinal cord regeneration; therapy development; transcription factor

DESCRIPTION (provided by applicant): The ability to regenerate structures and biological function would be of considerable value to a large number of patients. For many years experiments have focused on identifying what types of structures, in what organisms, undergo regeneration. More recently, studies have begun to identify signal transduction pathways that might be involved in regeneration. Among these pathways are those stimulated by the 19 members of the Wnt family of secreted ligands. Wnt signaling components are expressed during regeneration in multiple species but whether Wnt signaling is occurring and whether it is important for regeneration is unknown. Our specific aims seek to resolve the major outstanding questions regarding Wnts and regeneration. Aim 1: Is Wnt signaling activated during regeneration and if so, in which cells? Aim 2: Is Wnt signaling necessary for regeneration to occur, as determined by loss of function experiments? Aim 3: Can gain of function of Wnt signaling enhance regeneration? Finally, Aim 4 will seek to identify Wnt-responsive genes during regeneration and to study their roles in regeneration. By studying regeneration in Xenopus tadpoles, adult zebrafish, and the injured mouse spinal cord we have preliminary data supporting the first three aims, thereby establishing that Wnt signaling is indeed involved and functional in regeneration. The benefit of simultaneously employing frogs, fish, and mice in our project is that we can determine whether the roles of Wnt signaling in regeneration are conserved between species. Thus the general significance of the proposal is that we have a focused set of experiments that will reveal whether or not Wnt signaling is necessary and sufficient for stimulating regeneration in vertebrates. The immediate relevance to human medicine is that we directly test whether Wnt signaling improves the ability of neural stem cells to promote regeneration in a mouse model of spinal cord injury. This research therefore builds upon experiments in various model organisms to contribute to the development of therapies.

描述（由申请人提供）：再生结构和生物功能的能力对于大量患者来说具有相当大的价值。多年来，实验的重点是确定哪些类型的结构、哪些生物体可以进行再生。最近，研究已经开始确定可能参与再生的信号转导途径。这些途径中包括那些由 Wnt 分泌配体家族的 19 个成员刺激的途径。 Wnt 信号传导成分在多个物种的再生过程中表达，但 Wnt 信号传导是否正在发生以及它对再生是否重要尚不清楚。我们的具体目标是解决有关 Wnts 和再生的主要悬而未决的问题。目标 1：Wnt 信号传导在再生过程中是否被激活？如果是，在哪些细胞中激活？目标 2：根据功能丧失实验确定，Wnt 信号传导对于再生的发生是否是必需的？目标 3：Wnt 信号传导功能的获得可以增强再生吗？最后，目标 4 将寻求鉴定再生过程中的 Wnt 反应基因并研究它们在再生中的作用。通过研究非洲爪蟾蝌蚪、成年斑马鱼和受伤小鼠脊髓的再生，我们获得了支持前三个目标的初步数据，从而确定 Wnt 信号确实参与再生并发挥作用。在我们的项目中同时使用青蛙、鱼和小鼠的好处是，我们可以确定 Wnt 信号在再生中的作用在物种之间是否保守。因此，该提案的总体意义在于，我们进行了一组重点实验，将揭示 Wnt 信号传导对于刺激脊椎动物再生是否必要且充分。与人类医学直接相关的是，我们直接测试 Wnt 信号传导是否可以提高神经干细胞在脊髓损伤小鼠模型中促进再生的能力。因此，这项研究建立在各种模式生物实验的基础上，以促进治疗方法的开发。