BMP and FGF signaling in Mammalian Digit Regeneration

哺乳动物手指再生中的 BMP 和 FGF 信号传导

• 批准号: 7244985
• 负责人: KEN MUNEOKA
• 金额: $ 20.58万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-17 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244985
• 关键词: biological signal transduction; bone morphogenetic proteins; fibroblast growth factor; fingers; gene expression; gene mutation; genetic regulation; genetically modified animals; growth factor receptors; human immunodeficiency virus 1; laboratory mouse; limb regeneration; molecular biology; organ culture; skin; transcription factor; transfection /expression vector

DESCRIPTION (provided by applicant): 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, etc.), and in response to amputation, a perfect replica of the tip of the digit including the nail and fingerprint regenerates. Surprisingly little is in fact known about the digit regeneration process in humans, or other mammals, yet the potential for clinical impact seems reasonably high. Using a mouse model we provide evidence that BMP signaling and Msxl function is required for a successful regeneration response in the mouse fetal digit. In this application we propose studies to elucidate the mechanisms by which BMP signaling and Msxl activity regulates fetal digit regeneration. 4 specific aims are proposed. In the first aim we will explore the role of BMP signaling in the in vivo control of fetal digit regeneration by testing the hypothesis that endogenous BMP4 signaling is a regulator of regeneration. In the second aim we will utilize mutations of two type I BMP receptors (Bmpr-IA and Bmpr-IB) in combination with lentivirus mediated expression of constitutively active and dominant negative receptor forms to investigate the mechanism of BMP signaling in digit regeneration. In the third aim we will test the hypothesis that the transcriptional regulator Runx2/Cbfal functions downstream of Msxl and BMP4 in the regeneration response. In the fourth aim we focus on the role that Msxl plays in the formation of a regeneration competent wound epidermis. The long-term goal of this project is to understand the molecular requirements for digit regeneration with the intent of enhancing regenerative capabilities. The results from these studies will impact both clinical and basic sciences.

描述（由申请人提供）：很少有记录表明，人体器官能够通过完整和完美地替换受损部件对损伤做出反应。在适当的条件下，成年人的手指就是这样一个器官。手指由不同数量的不同细胞类型组成，这些细胞类型构成手指的各种组织（例如表皮、指甲、甲床、真皮、脂肪、骨等），作为对截肢的反应，包括指甲和指纹在内的指尖的完美复制品会再生。令人惊讶的是，事实上对人类或其他哺乳动物的手指再生过程知之甚少，但临床影响的潜力似乎相当高。使用小鼠模型，我们提供的证据表明，BMP信号和Msxl功能是所需的一个成功的再生反应，在小鼠胎儿指。在此应用中，我们提出的研究，以阐明BMP信号和Msxl活性调节胎儿手指再生的机制。提出了四个具体目标。在第一个目标中，我们将探索BMP信号在体内控制胎儿手指再生的作用，通过测试内源性BMP 4信号是再生的调节器的假设。在第二个目标中，我们将利用两种I型BMP受体（Bmpr-IA和Bmpr-IB）的突变结合慢病毒介导的组成型活性和显性负性受体形式的表达来研究BMP信号传导在指再生中的机制。在第三个目标中，我们将测试转录调节因子Runx 2/Cbfal在再生响应中在Msxl和BMP 4下游起作用的假设。在第四个目标中，我们专注于Msxl在形成再生能力的伤口表皮中发挥的作用。本项目的长期目标是了解手指再生的分子要求，以提高再生能力。这些研究的结果将影响临床和基础科学。