Mechanisms Underlying Tissue Fragility in Ectodermal Dysplasias

外胚层发育不良组织脆性的潜在机制

• 批准号: 9768892
• 负责人: Peter J. Koch
• 金额: $ 7.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768892
• 关键词: Adhesions; Affect; Antibodies; Binding; Binding Sites; Biologic Characteristic; Biological Assay; Biology; Cell Adhesion; Cell Differentiation process; Cell surface; Cell-Cell Adhesion; Cells; Complement; Complex; Data; Defect; Desmosomes; Development; Disease; Down-Regulation; Ectoderm; Ectodermal Dysplasia; Extracellular Matrix; Gene Expression; Genes; Genetic; Genetic Recombination; Goals; Hemidesmosomes; Homeostasis; Human; Impairment; Individual; Inherited; Integrins; Intercellular Junctions; Killer Cells; Lead; Ligands; Link; Mediating; Missense Mutation; Modeling; Molecular; Morphology; Mutation; Pathway interactions; Patients; Phenotype; Proteins; Proteome; Proteomics; Regulator Genes; Regulatory Element; Reporter; Role; SHFM1 gene; Signal Pathway; Signal Transduction; Site; Skin; Skin Abnormalities; Source; Structure; System; Testing; Tissues; base; developmental disease; experimental study; genome editing; induced pluripotent stem cell; innovation; insight; keratinocyte; keratinocyte differentiation; migration; molecular pathology; mouse model; mutant; novel strategies; patient subsets; protein complex; receptor; skin disorder; skin lesion; stem cell technology; therapeutic target; tool; transcription factor; transcriptome

TP63 is a transcription factor required for the normal development and homeostasis of the skin. Missense mutations in the TP63 gene are linked to a subset of severe developmental disorders, termed ectodermal dysplasias. Our application focuses on two of these, ankyloblepharon ectodermal dysplasia and clefting (AEC) and ectrodactyly ectodermal dysplasia and clefting (EEC), as they are each associated with severe skin erosions. Although EEC has historically not been associated with skin abnormalities, they do occur in a subset of patients (we refer to these patients as EEC/S patients). It is currently not clear how TP63-AEC or TP63-EEC/S mutations lead to the observed skin defects, specifically abnormalities in keratinocyte differentiation, cell- cell adhesion, and cell-extracellular matrix adhesion. While a few deregulated genes associated with AEC have been described, essentially nothing is known regarding the disease mechanism underlying EEC/S. The main goal of this application is to elucidate the cellular and molecular defects underlying AEC and EEC/S and to expand our understanding of the role of TP63 in normal keratinocyte biology. Based on our preliminary data, we hypothesize that desmosomal adhesion and hemidesmosomal adhesion are impaired in AEC and EEC/S patient skin, leading to the observed skin fragility. Further, our results suggest that impaired desmosomal signaling contributes to epidermal differentiation defects in patient skin. The current proposal will establish mechanistic insights into the molecular pathology underlying skin fragility in TP63-related ectodermal dypslasias. Further, we will gain new insights into the epidermal function of TP63, which will broaden our understanding of skin biology in general.

TP63是皮肤正常发育和稳态所需的转录因子。 TP63基因中的错义突变与严重发育障碍的一部分有关， 称为外胚层发育不良。我们的申请专注于其中两个，Ankyloblepharon 外皮发育不良和裂（AEC）和外皮外皮发育不良和裂口 （EEC），因为它们都与严重的皮肤侵蚀有关。虽然EEC历史上没有 与皮肤异常有关，它们确实发生在一部分患者中（我们是指这些 患者为EEC/S患者）。目前尚不清楚TP63-AEC或TP63-EEC/S突变如何 导致观察到的皮肤缺陷，特别是角质形成细胞分化的异常 细胞粘附和细胞 - 细胞基质粘附。而几个放松管制的基因相关 用AEC进行了描述，本质上，关于疾病机制一无所知 基础EEC/s。该应用的主要目标是阐明细胞和 AEC和EEC/S的分子缺陷，并扩展我们对 TP63在正常角质形成细胞生物学中的作用。根据我们的初步数据，我们 假设在AEC和 EEC/S患者皮肤，导致观察到的皮肤脆弱性。此外，我们的结果表明 脱粒信号受损受损会导致患者皮肤的表皮分化缺陷。 当前的提案将建立对基础分子病理学的机械见解 与TP63相关的外胚层dypslasias中的皮肤脆弱性。此外，我们将获得新的见解 TP63的表皮功能将扩大我们对皮肤生物学的理解。