R01:WNT AND BETA-CATENIN SIGNALING IN REGENERATION

描述（由申请人提供）： 再生结构和生物功能的能力对大量患者具有相当大的价值。多年来，实验一直专注于确定什么类型的结构，在什么生物体中，经历再生。最近，研究已经开始确定可能参与再生的信号转导途径。在这些途径中，是由分泌配体的Wnt家族的19个成员刺激的那些途径。Wnt信号传导组分在多个物种的再生过程中表达，但Wnt信号传导是否发生以及它对再生是否重要尚不清楚。我们的具体目标是寻求解决有关WNTs和再生的主要悬而未决的问题。目的1：Wnt信号在再生过程中是否被激活，如果是，在哪些细胞中？目的2：Wnt信号传导是否是再生发生所必需的，如功能丧失实验所确定的？目的3：Wnt信号转导功能的获得是否能促进再生？最后，目标4将寻求在再生过程中识别Wnt响应基因，并研究它们在再生中的作用。通过研究非洲爪蟾蝌蚪，成年斑马鱼和受伤的小鼠脊髓的再生，我们有初步的数据支持前三个目标，从而建立Wnt信号确实参与和功能的再生。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是否在物种之间是保守的。因此，该提议的一般意义在于，我们有一组集中的实验，将揭示Wnt信号传导是否是刺激脊椎动物再生所必需和充分的。与人类医学的直接相关性是，我们直接测试Wnt信号是否提高了神经干细胞促进脊髓损伤小鼠模型再生的能力。因此，这项研究建立在各种模式生物的实验基础上，有助于开发治疗方法。

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.