Mechanisms Underlying Tissue Fragility in Ectodermal Dysplasias

TP63是一种转录因子，是皮肤正常发育和动态平衡所必需的。 TP63基因的错义突变与严重发育障碍的子集有关， 称为外胚层发育不良。我们的应用程序集中在其中的两个方面，即眼睑僵硬 外胚层发育不良和外胚层分裂(AEC)和指趾外胚层发育不良和外胚层分裂 (EEC)，因为它们都与严重的皮肤侵蚀有关。尽管欧洲经济共同体在历史上并没有 与皮肤异常有关，它们确实发生在一部分患者中(我们指的是这些 患者为欧共体/S患者)。目前尚不清楚TP63-AEC或TP63-EEC/S是如何突变的 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- 细胞黏附、细胞-细胞外基质黏附。虽然一些不受管制的基因与 AEC已经被描述，基本上对疾病的机制一无所知 这个应用程序的主要目标是阐明细胞和 AEC和EEC/S背后的分子缺陷和扩大我们对 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 AEC和AEC中桥粒黏附和半桥粒黏附受损的假设 欧共体/S患者的皮肤，导致观察到的皮肤脆性。此外，我们的结果表明， 桥粒信号受损是患者皮肤表皮分化缺陷的原因之一。 目前的提议将建立对潜在的分子病理学的机械论见解 与TP63相关的外胚层发育迟缓患者的皮肤脆性。此外，我们还将对 TP63的表皮功能，这将拓宽我们对皮肤生物学的总体理解。

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.