Epigenetic predisposition and pathogenic mechanisms of recessive dystrophic epidermolysis bullosa

隐性营养不良性大疱性表皮松解症的表观遗传倾向和致病机制

• 批准号: 10453091
• 负责人: OLGA IGOUCHEVA
• 金额: $ 20.59万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453091
• 关键词: Address; Affect; Antibiotics; Attenuated; Bacterial Infections; Bandage; Basement membrane; Bulla; COL7A1; Cell Cycle Regulation; Collaborations; Collagen Type VII; Cream; Cutaneous; DNA Methylation; Data; Defect; Deformity; Dehydration; Dermal; Dermis; Development; Disease; Epidermis; Epidermolysis Bullosa Dystrophica; Epigenetic Process; Fibrosis; Functional disorder; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Heterogeneity; Histone Acetylation; Histone H3; Hypermethylation; Infection; Inherited; Injury; Intervention; Investigation; Lead; Link; Liquid substance; Malignant Neoplasms; Methylation; Minor; Molecular; Mucous Membrane; Mutation; NR0B2 gene; Nutrient; Organ; PTPN6 gene; Pain; Palliative Care; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Physicians; Play; Predisposition; Pruritus; Quality of life; Research; Role; Sepsis; Severities; Site; Skin; Squamous cell carcinoma; Symptoms; Testing; Therapeutic; Time; Tissues; Trauma; chronic wound; design; effective therapy; epigenetic regulation; healing; inhibitor; interest; keratinocyte; negative affect; non-healing wounds; programs; promoter; restoration; skin lesion; skin organogenesis; wound healing

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.

摘要 皮肤脆弱、愈合不良和慢性伤口的形成、纤维化和鳞状细胞癌 (SSC)是遗传性隐性遗传性营养不良性大疱性表皮松解症患者的共同特征 (RDEB)。这种疾病是由Col7A1基因突变引起的，这种突变会导致III型基因缺失或功能障碍 真皮与真皮的粘附性差，胶原蛋白含量低。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，并确定了导致RDEB死亡的因素 症状。目前尚不清楚为什么一些RDEB皮肤损伤可以愈合，而另一些则进展为不可愈合的伤口 在同一患者中，或者为什么在Col7A1基因中存在相同分子缺陷的患者可能会显著 不同的皮肤表现。在这里，我们假设RDEB中发生的表观遗传变化 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 在药物上减弱，以促进损伤后RDEB皮肤完整性的恢复和减少病态 后果。我们的初步数据显示H3组蛋白乙酰化显著减少 RDEB表皮中5-MC DNA甲基化水平及特定基因启动子的甲基化 RDEB来源的原代角质形成细胞参与纤维化、细胞周期控制和癌症的强烈支持 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。 在RDEB表皮中表达，概述靶基因，并确定与RDEB相关的分子机制(S) 表观遗传变化。在这个项目中，我们还将评估是否可以使用药物干预来 减少垂死因素，缓解垂死的RDEB症状。该项目的具体目标是：1) 研究表观遗传控制的分子机制、表观遗传变化和RDEB的特定靶点 2)探讨表观遗传学在RDEB发病机制中的作用，并评价其实用性。 使用表观遗传抑制剂来减少RDEB相关的皮肤表现。预计该项目的完成 将为我们提供关于表观遗传因素在生物多样性中的作用的关键信息。 RDEB，并阐明了更好地管理与RDEB相关的疼痛和垂死症状的途径 并将控制表观基因调控的分子通路定义为与伤口愈合、纤维化、 和鳞癌易感性。