LIMB REGENERATION IN HIGHER VERTEBRATES

高等脊椎动物的肢体再生

• 批准号: 6911942
• 负责人: KEN MUNEOKA
• 金额: $ 24.78万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911942
• 关键词: DNA binding protein; animal tissue; biological signal transduction; bone morphogenetic proteins; cell migration; developmental genetics; epidermal growth factor; fibroblast growth factor; gene expression; growth factor receptors; hyaluronate; limb regeneration; mutant; protein structure function; tissue /cell culture; vertebrate embryology

This application addresses the general problem of tissue and organ regeneration in higher vertebrates, including man. Our studies are guided by the general understanding that regeneration and development share similar mechanisms, and that regenerative ability is enhanced in the embryo and declines with developmental age. Our studies focus on regeneration of developing limb tissues using as models the chick limb bud and the mouse digit tip. These two regeneration models are distinct in that an innate regeneration response in the mouse lends itself to molecular genetic studies to uncover essential signaling pathways, whereas the chick limb bud, which lacks any regenerative ability whatsoever, can be induced to regenerate. Two of the four specific aims focus on the induction of a regeneration response in the chick limb bud (Aims 1 and 2), and the remaining two aims target our continuing effort to dissect signaling pathways important for fetal digit regeneration in the mouse (Aims 3 and 4). In aim 1 we will test the role that cell migration plays in the recruitment of cells to participate in the regeneration response. The induction of a regeneration response will be studied with respect to the role of 1) FGF4 signaling by the AER, 2) signaling by injured tissue to maintain AER function, and 3) a requirement of hyaluronan production. In aim 2 we will carry out functional studies to determine whether signaling involving Msx1 or ErbB1 is required for induced regeneration. Preliminary studies from the Dealy lab (Project 2) on ErbB 1, and recent studies with the mouse Msxl mutant suggest that these signaling pathways will play important roles in the regeneration response. In aim 3 we will extend our previous studies showing that BMP signaling is required for fetal digit tip regeneration. Targeting the type I Bmp receptors we will carry out loss of function and gain of function studies in cell transplantation assays in wildtype digits. These studies will determine whether BMP signaling essential for cells to participate in a regeneration response. In aim 4 we will investigate the role that Dlx5, a homeodomain protein expressed in the digit tip, plays in the regeneration response. Regeneration studies using the Dlx5 mutant and the Dlx5/6 double mutant digit will determine whether these Dlx genes are required for a regeneration response.

该应用解决了包括人在内的高脊椎动物中组织和器官再生的一般问题。我们的研究以一种普遍的理解为指导，即再生和发展具有相似的机制，并且在胚胎中增强了再生能力，并且随着发育年龄的增长而下降。我们的研究重点是使用AS模型的雏鸡芽和小鼠数字来再生肢体组织的再生 提示。这两个再生模型与众不同，因为小鼠中的先天再生反应借出了分子遗传研究以发现基本信号通路，而鸡肢芽（缺乏任何再生能力）可能会引起再生。四个具体目的中的两个重点是在小鸡肢芽中诱导再生反应（目标1和2），其余两个目标是针对我们继续努力剖析小鼠胎儿数字再生重要的信号通路的持续努力（Aims 3和4）。在AIM 1中，我们将测试细胞迁移在募集细胞参与细胞中的作用 再生反应。将研究诱导再生响应，以相对于1）AER的作用1）FGF4信号传导，2）受伤组织的信号传导以维持AER功能，以及3）透明质酸产生的需求。在AIM 2中，我们将进行功能研究，以确定诱导再生是否需要涉及MSX1或ERBB1的信号传导。 ERBB 1上Dealy Lab（项目2）的初步研究以及对小鼠MSXL突变体的最新研究表明，这些信号传导途径将在再生反应中起重要作用。在AIM 3中，我们将扩展以前的研究，表明胎儿数字尖端再生需要BMP信号传导。针对I型BMP受体，我们将损失 野生型数字中细胞移植测定中功能研究的功能和功能研究。这些研究将确定细胞参与再生反应的BMP信号传导是否必不可少。在AIM 4中，我们将研究DLX5在数字尖端中表达的同源域蛋白DLX5在再生反应中发挥作用。使用DLX5突变体和DLX5/6双突变体数字的再生研究将确定这些DLX基因是否需要再生反应。