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: 9976326
• 负责人: Peter J. Koch
• 金额: $ 42.93万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976326
• 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是皮肤正常发育和体内平衡所必需的转录因子。