The role of p63 in normal epidermal differentiation and ectodermal dysplasias

p63是一种表达为6种亚型的转录因子，其显性突变是皮肤脆弱综合征强直性睑球外胚层发育不良和脱脱（AEG）的基础。Delta-Np63表达减少的小鼠出现类似AEG患者的皮肤糜烂。拟议的研究将剖析Delta-Np63控制正常表皮稳态的调控途径，并将深入了解AEG的疾病机制。我们最近发现Fras1和Galml4是Delta-Np63的直接转录靶点。这些基因的错误表达可能导致AEG表型。为了进一步研究这些基因在胚胎和出生后皮肤中的作用，我们将开发改变这些基因表达的小鼠模型。这些小鼠模型将使我们能够确定Frasi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功能的分析将通过蛋白质组学和微阵列分析来完成。最终，提出的研究将有助于我们理解导致AEG患者皮肤脆弱的分子机制，并可能确定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.