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.

抽象的 皮肤的脆弱性，愈合不佳和慢性伤口的发育，纤维化和鳞状细胞癌 （SSC）是患有遗传性遗传性营养不良的表皮溶液的患者的常见特征 （rdeb）。该疾病是由Col7a1基因突变引起的，导致VII型缺乏或功能障碍 表皮对真皮的胶原蛋白和不良锚固。多次调查，包括我们小组的研究 解决了RDEB的病理生理学和治疗，并定义了有助于RDEB Moribund的因素 症状。目前尚不清楚某些RDEB皮肤病变为何愈合，而其他疾病的进展 在同一患者中，或者为什么在Col7a1基因中携带相同分子缺陷的患者可能急剧 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SCC发育，表观遗传变化可能是 在药理学上衰减以促进损伤后RDEB皮肤完整性的恢复和病态减少 结果。我们的初步数据显示H3组蛋白乙酰化大幅度降低和非常重要的 RDEB表皮中的5-MC DNA甲基化水平以及特定基因启动子的甲基化水平 参与纤维化，细胞周期控制和癌症的主要rdEB衍生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定义基因表观遗传调节的作用 在RDEB表皮，概述靶基因和定义负责的分子机制中的表达 表观遗传变化。在这个项目中，我们还将评估药理学干预措施是否可以用于 减少垂死因素并减轻垂死的RDEB症状。该项目的具体目的是：1） 研究表观遗传控制，表观遗传变化和RDEB的特定靶标的分子机制 表皮; 2）研究表观遗传学对RDEB发病机理的贡献并评估效用 表观遗传学抑制剂，以减少与RDEB相关的皮肤表现。预计完成 当前项目将为我们提供有关表观遗传因素在 rdeb，并阐明了更好地管理RDEB相关的痛苦和垂死的表现的道路 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敏感性。