The role of p63 in normal epidermal differentiation and ectodermal dysplasias

p63 在正常表皮分化和外胚层发育不良中的作用

• 批准号: 8082625
• 负责人: Maranke I. Koster
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-14 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082625
• 关键词: Award; Basement membrane; Binding Proteins; Defect; Development; Disease; Ectodermal Dysplasia; Embryo; Embryonic Development; Epidermis; Gene Expression; Gene Targeting; Genes; Genetically Engineered Mouse; Grant; Homeostasis; Lead; Microarray Analysis; Molecular; Morphogenesis; Mus; Mutation; Patients; Phase; Phenotype; Process; Protein Binding; Protein Isoforms; Proteins; Proteomics; Regulatory Pathway; Role; Skin; Skin Abnormalities; Staging; Stratification; Syndrome; Transactivation; insight; keratinocyte; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; phase change; postnatal; research study; transcription factor

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.

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缺陷（AEG）的基础。类似于AEG患者中发现的皮肤糜烂在Delta-Np 63表达降低的小鼠中发展。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AEG潜在疾病机制的深入了解。我们最近确定Fras 1和Galml 4作为Delta-Np 63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，我们将开发这些基因表达改变的小鼠模型。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Calml 4在表皮终末分化中的作用。我们将通过进行蛋白质组学和微阵列分析来完成对Calml 4在角质形成细胞终末分化中的功能的分析。最终，拟议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，并可能确定旨在治疗这种疾病的新治疗方法的靶点。