Epigenetic predisposition and pathogenic mechanisms of recessive dystrophic epidermolysis bullosa

摘要 皮肤脆弱，伤口愈合不良和慢性伤口，纤维化和鳞状细胞癌的发展 (SSC)是遗传性隐性营养不良性大疱性表皮病患者的常见特征 （RDEB）。该病是由Col 7A 1基因突变引起的，其导致VII型缺乏或功能障碍 胶原和表皮与真皮的锚定差。多项调查，包括我们小组的研究， 讨论了RDEB的病理生理学和治疗，并定义了导致RDEB濒死的因素 症状目前还不清楚为什么有些RDEB皮肤病变愈合，而其他进展为不愈合的伤口 在同一患者中，或者为什么Col 7A 1基因中具有相同分子缺陷的患者可能会发生严重的 不同的皮肤表现。在这里，我们假设发生在RDEB中的表观遗传变化 表皮影响伤口愈合、纤维化和鳞状细胞癌的发展，表观遗传变化可能是 减轻RDEB，以促进损伤后RDEB皮肤完整性的恢复， 后果我们的初步数据显示H3组蛋白乙酰化显著降低， RDEB表皮中5-mC DNA甲基化水平以及特定基因启动子的甲基化 参与纤维化，细胞周期控制，和癌症的主要RDEB衍生的角质形成细胞强烈支持 提出的假设。我们的探索性项目旨在确定基因的表观遗传调控的作用， RDEB表皮中的表达，概述靶基因，并定义负责RDEB表皮中的分子机制。 表观遗传变化在这个项目中，我们还将评估药物干预是否可以用于 减少濒死因素和减轻濒死RDEB症状。该项目的具体目标是：1） 研究RDEB中表观遗传控制、表观遗传变化和特异性靶点的分子机制 研究表观遗传学在RDEB发病机制中的作用，并评估表观遗传学在RDEB发病机制中的作用。 表观遗传抑制剂，以减少RDEB相关的皮肤表现。预计完工后， 本项目的研究将为我们提供有关表观遗传因素在 RDEB，并阐明更好地管理RDEB相关疼痛和濒死表现的途径 并将控制表观遗传基因调节的分子途径定义为与伤口愈合，纤维化， 和SCC易感性。

Abstract Fragility of the skin, development of poorly healing and chronic wounds, fibrosis, and squamous cell carcinoma (SSC) are common features in patients suffering from hereditary Recessive Dystrophic Epidermolysis Bullosa (RDEB). The disease is caused by mutations in Col7A1 gene, which lead to lack or dysfunction of type VII collagen and poor anchorage of epidermis to dermis. Multiple investigations, including studies from our group, addressed both RDEB pathophysiology and therapy, and defined factors contributing to RDEB moribund symptoms. It remains unclear why some RDEB skin lesions heal, while other progress to non-healing wounds in the same patient, or why patients harboring same molecular defect in Col7A1 gene may have drastically different cutaneous manifestations. Here, we hypothesize that epigenetic changes occurring in RDEB epidermis affect wound healing, fibrosis, and SCC development and that epigenetic changes could be pharmacologically attenuated to facilitate restoration of RDEB skin integrity after injury and reduction of morbid consequences. Our preliminary data showing drastically reduced H3 histone acetylation and highly significant levels of 5-mC DNA methylation in the RDEB epidermis as well as methylation of promoters of specific genes involved in fibrosis, cell cycle control, and cancer in the primary RDEB-derived keratinocytes strongly support proposed hypothesis. Our exploratory project is designed to define the role of epigenetic regulation of gene expression in RDEB epidermis, outline target genes, and define molecular mechanism(s) responsible for epigenetic changes. In this project, we will also assess whether pharmacological intervention can be used to lessen moribund factors and alleviate moribund RDEB symptoms. The Specific Aims of the project are: 1) To investigate molecular mechanism of epigenetic control, epigenetic changes, and specific targets in RDEB epidermis; and 2) To investigate the contribution of epigenetics to RDEB pathogenesis and evaluate the utility of epigenetic inhibitors to reduce RDEB-associated cutaneous manifestations. It is anticipated that completion of the current project will provide us with the crucial information regarding the role of epigenetic factors in RDEB, and illuminate the path to better management of RDEB-associated painful and moribund manifestations and define molecular pathways controlling epigenetic gene regulation as relevant to wound healing, fibrosis, and SCC susceptibility.