Mechanisms Underlying Tissue Fragility in Ectodermal Dysplasias

TP 63是皮肤正常发育和稳态所需的转录因子。 TP 63基因中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。我们的应用集中在其中的两个， 外胚层发育不良和裂（AEC）和缺指（趾）外胚层发育不良和裂 (EEC)因为它们都与严重的皮肤糜烂有关。虽然欧洲经济共同体历史上没有 与皮肤异常有关，它们确实发生在一部分患者中（我们将这些患者称为 患者为EEC/S患者）。目前尚不清楚TP 63-AEC或TP 63-EEC/S突变是如何导致 导致观察到的皮肤缺陷，特别是角质形成细胞分化、细胞- 细胞粘附和细胞-细胞外基质粘附。一些失调的基因 与AEC已经被描述，基本上没有什么是已知的有关疾病的机制 基础EEC/S。本申请的主要目标是阐明细胞和 AEC和EEC/S潜在的分子缺陷，并扩大我们对 TP 63在正常角质形成细胞生物学中的作用。根据初步数据，我们 假设AEC中桥粒粘附和半桥粒粘附受损， EEC/S患者皮肤，导致观察到的皮肤脆性。此外，我们的研究结果表明， 受损的桥粒信号传导导致患者皮肤中的表皮分化缺陷。 目前的建议将建立机制的见解分子病理学基础 TP 63相关外胚层发育不良中的皮肤脆弱性。此外，我们将获得新的见解， TP 63的表皮功能，这将拓宽我们对皮肤生物学的理解。

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.