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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

基本信息

批准号：
7920511
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
项目类别：
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/7920511
关键词：
Adult Alleles Award Basement membrane Binding Proteins Bulla Cattle Cultured Cells DNA Data Defect Development Disease Down-Regulation Ectodermal Dysplasia Embryo Embryonic Development Epidermis Failure Gene Expression Gene Targeting Generations Genes Genetic Recombination Genetically Engineered Mouse Goals Grant Hand Homeostasis Human Intention Knockout Mice LacZ Genes Lead Masks Microarray Analysis Molecular Morphogenesis Mus Mutation Natural regeneration Neonatal Patients Pattern Phase Phenotype Process Progress Reports Protein Binding Protein Isoforms Proteins Proteomics RU-486 Regulatory Pathway Research Design Role Signal Transduction Site Skin Skin Abnormalities Staging Stratification Syndrome System Testing Transactivation Transcript Transgenic Mice Update Vertebral column embryonic stem cell in utero insight keratinocyte mouse model novel novel therapeutic intervention novel therapeutics overexpression phase change postnatal premature promoter repository research study response transcription factor

项目摘要

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 是一种以六种亚型表达的转录因子，其显性突变是皮肤脆性综合征、踝睑外胚层发育不良和脱垂 (AEG) 的基础。 Delta-Np63 表达减少的小鼠会出现类似于 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节途径，并将深入了解 AEG 的疾病机制。我们最近确定 Fras1 和 Galml4 作为 Delta-Np63 的直接转录靶标。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发生改变的小鼠模型。这些小鼠模型将使我们能够确定 Frasi 在调节产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。我们对角质形成细胞终末分化中 Calml4 功能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。