BMP and FGF signaling in Mammalian Digit Regeneration

描述(由申请人提供)：很少有文献记载人体器官能够通过完全和完美地替换受损部分来对损伤做出反应。在适当的条件下，成人的指头就是这样一个器官。手指由多种不同的细胞类型组成，构成手指的各种组织(例如，表皮、指甲、甲床、真皮、脂肪、骨骼等)，并且作为对截肢的响应，包括指甲和指纹在内的指尖的完美复制品重新生成。令人惊讶的是，人们对人类或其他哺乳动物的手指再生过程知之甚少，但临床影响的可能性似乎相当高。使用小鼠模型，我们提供了BMP信号和Msx1功能是小鼠胚胎手指成功再生反应所必需的证据。在这一应用中，我们建议进行研究，以阐明BMP信号和Msx1活性调节胎儿手指再生的机制。提出了4个具体目标。在第一个目标中，我们将通过检验内源性BMP4信号是再生调节因子的假设，来探讨BMP信号在体内控制胎儿手指再生中的作用。在第二个目的中，我们将利用两种I型BMP受体(Bmpr-IA和Bmpr-IB)的突变，结合慢病毒介导的结构性活性和显性负性受体形式的表达，来研究BMP信号在手指再生中的机制。在第三个目的中，我们将检验转录调控因子Runx2/Cbfal在Msx1和BMP4下游参与再生反应的假设。在第四个目标中，我们重点研究了Msx1在具有再生能力的伤口表皮形成中所起的作用。该项目的长期目标是了解手指再生的分子需求，目的是增强再生能力。这些研究的结果将对临床和基础科学产生影响。

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.