MSX GENES IN WOUND HEALING AND REGENERATION

MSX 基因在伤口愈合和再生中的作用

• 批准号: 2026558
• 负责人: KEN MUNEOKA
• 金额: $ 14.85万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2026558
• 关键词: amputation; cell biology; cell type; cytogenetics; fingers; gene expression; homeobox genes; immunocytochemistry; in situ hybridization; laboratory mouse; microinjections; molecular genetics; musculoskeletal imaging /visualization /scanning; musculoskeletal regeneration; polymerase chain reaction; regulatory gene; scars; skin derivative; transforming growth factors; video recording system; wound healing

There are few documented instances in which human organs are able to respond to injury by complete and perfect replacement of the damaged parts. Under the appropriate conditions the adult digit is one such organ. The digit is composed of a diverse number of distinct cell types making up the various tissues of the digit (e.g. epidermis, nail, nailbed, dermis, adipose, bone), and in response to amputation, a perfect replica of the tip of the digit including the nail and fingerprint regenerates. This regeneration response is level-specific and only occurs following amputations at the level of the nailbed. An additional aspect of digit regeneration is that wound healing occurs without the deposition of scar tissue, whereas wound healing of amputations just proximal to the nailbed (regeneration-incompetent) results in scar tissue formation. Thus, digit amputation in mammals represents a model system to study both organ regeneration and scar-free wound healing. It is therefore surprising that there has been little interest in studying this remarkable phenomenon, despite the fact that the most frequent body part injured is the hand and that in the US approximately 19,00() people experience loss of a digit in any one year. The best model for digit regeneration is the mouse digit and using this system we have initiated the first molecular characterization of digit formation and regeneration. Digit regeneration is associated with the presence nailbed tissue at the wound and we show that two homeobox- containing genes (Msx1 and Msx2) are expressed by nailbed cells and also during regeneration. Recently both of these genes have been knockout in the lab of Dr. Richard Maas. In collaboration with Dr. Maas I propose to utilize these mutant strains to investigate the role of the nailbed and the Msx genes in the control of digit regeneration and wound healing. Because the Msx mutant mice do not survive to adulthood, we will conduct these experiments on digits that develop ectopically following exo-utero grafting of mutant digit rudiments onto wild type embryos. The specific aims include l) characterizing the regeneration-inducing capacity of nailbed tissue, 2) characterizing the role of nailbed cells in wound healing following amputation, 3) characterizing post-natal development, regenerative potential and wound healing of Msx1-/- mutant mice, Msx2-/- mutant mice, and Msx1-/-/Msx2-/-double mutant mice.

很少有记录表明人体器官能够 通过完整、完美地替换受损部位来应对伤害 部分。在适当的条件下，成人的手指就是这样的一种 器官。该数字由多种不同的细胞类型组成 组成手指的各种组织（例如表皮、指甲、 甲床、真皮、脂肪、骨骼），并且为了应对截肢，一个完美的 手指尖的复制品，包括指甲和指纹 再生。这种再生反应是特定于水平的并且仅发生 在甲床水平截肢后。另一个方面 手指再生的关键在于伤口愈合无需沉积 疤痕组织的愈合，而截肢的伤口愈合仅接近于 甲床（再生能力差）导致疤痕组织形成。 因此，哺乳动物的手指截肢代表了研究两者的模型系统 器官再生和无疤痕伤口愈合。因此是 令人惊讶的是，人们对此研究兴趣不大 值得注意的现象，尽管事实上最常见的身体部位 受伤的是手，在美国大约有 19,00() 人 在任何一年中都会失去一位数字。 手指再生的最佳模型是鼠标手指并使用它 系统我们已经启动了数字的第一个分子表征 形成和再生。数字再生与 伤口处存在甲床组织，我们发现两个同源盒- 含有基因（Msx1 和 Msx2）的甲床细胞表达，并且 再生期间。最近这两个基因都已被敲除 理查德·马斯博士的实验室。我建议与马斯博士合作 利用这些突变株来研究甲床的作用和 Msx 基因控制手指再生和伤口愈合。 由于Msx突变小鼠无法存活到成年，我们将进行 这些实验是针对在子宫外发育的手指进行的 将突变的手指雏形移植到野生型胚胎上。具体的 目标包括 l) 表征再生诱导能力 甲床组织，2) 表征甲床细胞在伤口中的作用 截肢后的愈合，3) 表征产后发育， Msx1-/- 突变小鼠、Msx2-/- 的再生潜力和伤口愈合 突变小鼠和Msx1-/-/Msx2-/-双突变小鼠。