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: 10673176
• 负责人: OLGA IGOUCHEVA
• 金额: $ 17.16万
• 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/10673176
• 关键词: Address; Affect; Antibiotics; Attenuated; Bacterial Infections; Bandage; Basement membrane; Bulla; COL7A1; Cell Cycle Regulation; Collaborations; Collagen; Collagen Type VII; Common Carcinoma; 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; 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; 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; forging; healing; inhibitor; interest; keratinocyte; negative affect; non-healing wounds; pharmacologic; programs; promoter; restoration; skin lesion; 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.

抽象的 皮肤脆弱、愈合不良和慢性伤口、纤维化和鳞状细胞癌 (SSC) 是遗传性隐性营养不良性大疱性表皮松解症患者的常见特征 （RDEB）。该病是由于Col7A1基因突变，导致VII型缺乏或功能障碍所致 胶原蛋白和表皮与真皮的锚定不良。多项调查，包括我们小组的研究， 阐述了 RDEB 病理生理学和治疗，并明确了导致 RDEB 濒临死亡的因素 症状。目前尚不清楚为什么一些 RDEB 皮肤损伤能够愈合，而另一些则进展为不愈合伤口 在同一名患者身上，或者为什么具有相同 Col7A1 基因分子缺陷的患者可能会出现严重的症状 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 药理学上减弱，以促进受伤后 RDEB 皮肤完整性的恢复并减少病态 结果。我们的初步数据显示 H3 组蛋白乙酰化显着降低并且非常显着 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 参与初级 RDEB 衍生角质形成细胞中的纤维化、细胞周期控制和癌症，强烈支持 提出的假设。我们的探索性项目旨在定义基因表观遗传调控的作用 RDEB 表皮中的表达，概述目标基因，并定义负责的分子机制 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 减少垂死因素并缓解垂死 RDEB 症状。该项目的具体目标是： 1) 研究 RDEB 中表观遗传控制、表观遗传变化和特定靶标的分子机制 表皮; 2) 研究表观遗传学对 RDEB 发病机制的贡献并评估其实用性 表观遗传抑制剂可减少 RDEB 相关的皮肤表现。预计完成 当前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 相关疼痛和垂死表现的道路 并定义控制与伤口愈合、纤维化、 和 SCC 敏感性。