P63 Network in Pathogenesis of Ectodermal Dysplasia

P63 网络在外胚层发育不良发病机制中的作用

• 批准号: 6877968
• 负责人: ALEXEY FOMENKOV
• 金额: $ 13.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877968
• 关键词: RNA splicing; cell differentiation; cell proliferation; clinical research; congenital skin disorder; fibroblast growth factor; functional /structural genomics; genetically modified animals; growth factor receptors; human genetic material tag; human tissue; keratinocyte; laboratory mouse; microarray technology; molecular pathology; p53 gene /protein; protein isoforms; protein localization; protein protein interaction; protein sequence; protein structure function; proteomics; tissue /cell culture

DESCRIPTION (provided by applicant): We hypothesize that p63 functions through physical and functional interaction with other cellular proteins contributing in regulation of cell proliferation, differentiation and pathogenesis of skin-related disorders. We recently demonstrated that p63alpha associates with RNA processing molecular machinery through binding to ABBP1 and SCAF4 proteins that leads to regulation of the fibroblast growth factor receptor (FGFR)-2 RNA splicing towards epithelial-specific FGFR-2 isoform. We suggest that this post-transcriptional regulatory mechanism contributes to pathogenesis of AEC syndrome, which might represent dysregulation of epithelial/mesenchymal differentiation program. To support our hypothesis, we will perform the following Specific Aims: (1) to analyze the physical association and subcellular colocalization between p63alpha and RNA splicing proteins (ABBP1 and SCAF4/rA4) in keratinocytes and primary epithelial/skin cultures (epidermal dysplasia); (2) to study the functional effect of p63/ABBP1/SCAF4 complexes on FGFR-2 splicing in ectodermal dysplasia; (3) to evaluate the effect of p63/ABBP1/SCAF4 complexes on gene target expression in keratinocytes and primary epithelial cultures. We will use modern molecular biology approaches of functional genomics and proteomics including protein-protein interaction analysis and DNA microarray analysis/promoter analysis.

描述（由申请人提供）：我们假设p63通过与其他细胞蛋白的物理和功能相互作用来起作用，这些细胞蛋白有助于调节细胞增殖，分化和皮肤相关疾病的发病机理。我们最近证明，p63alpha通过与ABBP1和SCAF4蛋白结合而与RNA处理分子机械相关联，从而导致对成纤维细胞生长因子受体（FGFR）-2 RNA剪接朝向上皮特异性FGFR-2同工型的调节。我们建议这种转录后调节机制有助于AEC综合征的发病机理，这可能代表上皮/间质分化程序的失调。 为了支持我们的假设，我们将执行以下特定目的：（1）分析p63alpha和RNA剪接蛋白（ABBP1和SCAF4/RA4）之间的物理关联和亚细胞共定位，并在角质形成细胞中和原发性上皮/皮肤培养（表皮培养物）中分析p63alpha和RNA剪接蛋白（ABBP1和SCAF4/RA4）； （2）研究p63/abbp1/scaf4复合物对外胚层发育不良中FGFR-2剪接的功能效应； （3）评估p63/abbp1/scaf4复合物对角质形成细胞和原发性上皮培养物中基因靶标表达的影响。 我们将使用功能基因组学和蛋白质组学的现代分子生物学方法，包括蛋白质 - 蛋白质相互作用分析和DNA微阵列分析/启动子分析。