The role of p63 in normal epidermal differentiation and ectodermal dysplasias

P63是一种转录因子，表达为六种异构体，它的显性突变是皮肤脆性综合征强直睑外胚层发育不良和脱垂(AEG)的基础。与AEG患者相似的皮肤侵蚀在Delta-Np63表达降低的小鼠中发生。这项拟议的研究将剖析Delta-Np63控制正常表皮动态平衡的调控途径，并将为深入了解AEG的发病机制提供依据。我们最近确定Fras1和Galm14是Delta-Np63的直接转录靶点。这些基因的错误表达可能与AEG的表型有关。为了进一步研究这些基因在胚胎和出生后皮肤中的作用，我们将开发这些基因表达发生变化的小鼠模型。这些小鼠模型将使我们能够确定FRAASI在调节出生后表皮基底膜完整性中的作用。此外，我们将使用这些小鼠模型来确定Calml4在表皮终末分化中的作用。我们对Calml4在角质形成细胞终末分化中的作用的分析将通过蛋白质组学和微阵列分析来完成。最终，拟议的研究将有助于我们了解导致AEG患者皮肤脆弱的分子机制，并可能确定旨在治疗这种疾病的新治疗方法的靶点。

Dominant mutations in p63, a transcription factor expressed as six isoforms, underlie the skin fragility syndrome ankyloblepharon ectodermal dysplasia and defting (AEG). Skin erosions that resemble those found in AEG patients develop in mice with reduced Delta-Np63 expression. The proposed studies will dissect the regulatory pathways by which Delta-Np63 controls normal epidermal homeostasis and will provide insight into the disease mechanism underlying AEG. We have recently identified Fras1 and Galml4 as direct transcriptional targets of Delta-Np63. Misexpression of these genes may contribute to the AEG phenotype. To further study the role of these genes in embryonic and postnatal skin, we will develop mouse models in which the expression of these genes is altered. These mouse models will allow us to determine the role of Frasi in regulating basement membrane integrity in postnatal epidermis. Furthermore, we will use these mouse models to determine the role of Calml4 in epidermal terminal differentiation. Our analysis of Calml4 function in keratinocyte terminal differentiation will be completed by performing proteomics and microarray analysis. Ultimately, the proposed studies will contribute to our understanding of the molecular mechanisms that cause skin fragility in AEG patients, and may identify targets for novel therapeutic approaches aimed at treating this disease.