The role of p63 in normal epidermal differentiation and ectodermal dysplasias

描述（由申请人提供）： 项目摘要：p63是一种表达为六种亚型的转录因子，其显性突变是皮肤脆性综合征、睑粘连性外胚层发育不良和裂（AEC）的基础。我最近发现，在Delta-Np 63表达减少的小鼠中，出现了类似于AEC患者的皮肤糜烂。拟议的研究将剖析Delta-Np 63控制正常表皮稳态的调节途径，并将提供对AEC潜在疾病机制的深入了解。使用基因表达谱，我已经确定了三个推定的Delta-Np 63靶基因，Fras 1，Frem 2和Calml 4，其错误表达可能有助于AEC表型。在该奖项的指导阶段，我将确定Delta-Np 63 α是否直接调节基底膜组分Frasl和Frem 2的表达。此外，我将确定是否Delta-Np 63 α调节角质形成细胞的分化，直接诱导预测的钙结合蛋白Calml 4的表达。这些研究将在贝勒医学院的Dennis Roop博士的实验室进行，该实验室具有杰出的研究和指导年轻科学家的悠久历史。作为一个独立的研究者，我将产生诱导型小鼠模型，其中Frasl，Frem 2或Calml 4的表达可以在表皮中下调。这些小鼠模型将使我能够确定Frasl和Frem 2在调节出生后表皮基底膜完整性中的作用。此外，我将使用这些小鼠模型来确定Calml 4在表皮终末分化中的作用。我对CalirM在角质形成细胞终末分化中的功能的分析将通过进行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理解导致AEC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。 相关性：皮肤脆性疾病（AEC综合征）患者的皮肤糜烂是由一种名为p63的基因突变引起的。我们最近开发了这种疾病的小鼠模型，这将使我们能够确定p63缺陷如何导致皮肤糜烂。这些研究可能会导致开发新的治疗策略，这种疾病和其他疾病的特点是脆弱的皮肤。

DESCRIPTION (provided by applicant): Project Summary: Dominant mutations in p63, a transcription factor expressed as six isoforms, underlie the skin fragility syndrome ankyloblepharon ectodermal dysplasia and clefting (AEC). I recently discovered that skin erosions that resemble those found in AEC 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 AEC. Using gene expression profiling, I have identified three putative Delta-Np63 target genes, Frasl, Frem2, and Calml4, whose misexpression may contribute to the AEC phenotype. During the mentored phase of the award I will determine if Delta-Np63alpha directly regulates expression of the basement membrane components Frasl and Frem2. In addition, I will determine if Delta-Np63alpha regulates keratinocyte differentiation by directly inducing expression of the predicted calcium-binding protein Calml4. These studies will be performed in the laboratory of Dr. Dennis Roop at Baylor College of Medicine, which has a long history of outstanding research and mentorship of young scientists. As an independent investigator, I will generate inducible mouse models in which expression of Frasl, Frem2, or Calml4 can be downregulated in the epidermis. These mouse models will allow me to determine the role of Frasl and Frem2 in regulating basement membrane integrity in postnatal epidermis. Furthermore, I will use these mouse models to determine the role of Calml4 in epidermal terminal differentiation. My analysis of CalirM 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 AEC patients, and may identify targets for novel therapeutic approaches aimed at treating this disease. Relevance: Skin erosions in patients with a skin fragility disease, AEC syndrome, are caused by mutations in a gene called p63. We have recently developed a mouse model for this disease, which will allow us to determine how defects in p63 cause skin erosions. These studies may lead to the development of novel therapeutic strategies for this disease and other diseases characterized by fragile skin.