The role of Slug in cutaneous reepithelialization

描述(由申请人提供)：有效的伤口修复需要不同细胞类型、途径和过程的复杂和综合的相互作用。再上皮化和屏障功能的恢复是成功愈合的一个必要条件，也是慢性伤口被破坏的一个过程。遗传模型对于确定影响伤口愈合的特定方面的基因至关重要，我们已经获得证据表明，发育转录因子slug/Snail2在体外、体外和体内都是上皮细胞生长的关键调节因子。Slug和蜗牛蛋白家族的其他成员与发育和癌症中黏附和迁移的调节有关。胚胎中伤口修复和发育过程之间的相似性正受到越来越多的关注，特别是在共享调控途径的可能性方面。根据我们的证据，鼻涕虫可能有助于成人表皮的再生过程，本项目将调查鼻涕虫对伤口边缘角质形成细胞生长的影响。我们的总体项目目标是了解伤口边缘角质形成细胞在再上皮化过程中表型可塑性的调节机制，并通过这样做，阐明在伤口愈合受损的情况下可能存在缺陷的过程。在这项建议中，我们的目标是阐明由鼻涕虫控制的伤口边缘的事件。我们假设，在伤口边缘观察到的部分和可逆的上皮-间充质转化过程中，粘液在调节中起着中心作用。为了验证这一假设，我们将使用粘蛋白缺乏的遗传模型来1)确定粘蛋白在导致细胞增殖和迁移的角质形成细胞激活程序中的功能作用，2)使用微阵列方法建立粘蛋白在再上皮化中的作用的分子定义，以及3)使用正常和受损伤口愈合的模型来确定粘蛋白的高表达是否增强了体内的创伤修复。这些研究将提供有关鼻涕虫对成功上皮化所需的功能和表型可塑性的贡献的信息。了解正常伤口修复中的关键调控机制可能会为临床干预导致创伤愈合受损的医疗条件找到新的途径。

DESCRIPTION (provided by applicant): Effective wound repair requires a complex and integrated interplay of different cell types, pathways, and processes. Reepithelialization and restoration of barrier function is one requirement for successful healing and a process that is disrupted in chronic wounds. Genetic models have been pivotal for identification of genes that impinge on specific aspects wound healing, and we have obtained evidence that the developmental transcription factor Slug/Snail2 is a key regulator of epithelial outgrowth in vitro, ex vivo and in vivo. Slug and other members of the Snail family of proteins have been associated with regulation of adhesion and migration in development and cancer. The similarities between wound repair and developmental processes in the embryo are receiving increased attention, particularly with regard to the potential for shared regulatory pathways. Based on our evidence that Slug may contribute to regenerative processes in adult epidermis, this project will investigate the impact of Slug on keratinocyte outgrowth at wound borders. Our overall project goal is to understand mechanisms regulating the phenotypic plasticity of keratinocytes at wound margins during reepithelialization, and in doing so, shed light on processes that may be defective under conditions of impaired wound healing. In this proposal, our goal is to elucidate the events at the wound margin that are governed by Slug. We hypothesize that Slug plays central roles in regulating the partial and reversible epithelial-mesenchymal transition observed at wound margins. To test this hypothesis we will use a genetic model of Slug deficiency to 1) define the functional role of Slug in the keratinocyte activation program leading to cell proliferation and migration, 2) establish a molecular definition for the role of Slug in reepithelialization using microarray approaches and 3) establish whether elevated Slug expression augments wound repair in vivo using models of normal and impaired wound healing. These studies will provide information on the contributions of Slug to the functional and phenotypic plasticity required for successful reepithelialzation. Understanding key regulatory mechanisms in normal wound repair may identify new avenues for clinical intervention in medical conditions leading to impaired wound healing.