Epigenetic Regulation of Skin Regeneration

皮肤再生的表观遗传调控

• 批准号: 10494659
• 负责人: Christine Guo Lian
• 金额: $ 59.2万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494659
• 关键词: 3-Dimensional; ATAC-seq; Age; Aging; Animals; Area; Bioinformatics; Biological Markers; Biological Models; Biology of Aging; Cell Cycle Kinetics; Cells; Characteristics; Chromatin Structure; Chronology; Cicatrix; Clinical; Collaborations; Complex; CpG Islands; Cutaneous; DNA; DNA Methylation; Data; Dermal; Dermatopathology; Development; Enzymes; Epigenetic Process; Experimental Models; Family; Fibroblasts; Foundations; Gene Expression Profile; Genes; Genetically Engineered Mouse; Goals; Hair follicle structure; Health; Human; Image Analysis; Impaired wound healing; Maintenance; Mediating; Mesenchymal Stem Cells; Metabolic; Methylation; Modification; Morbidity - disease rate; Morphology; Mus; Nature; Neoadjuvant Therapy; Pattern; Play; Polycomb; Pre-Clinical Model; Premature aging syndrome; Process; Promoter Regions; Recording of previous events; Regulation; Rejuvenation; Reporting; Research Personnel; Resolution; Role; Site; Skin; Skin Aging; Skin Cancer; Testing; Therapeutic Effect; Time; Tissues; Transgenic Organisms; Untranslated RNA; Vision; Wound models; Xenograft procedure; age related; base; bioprinting; cell age; cell type; chronic wound; demethylation; epidermal stem cell; epigenetic regulation; experience; functional restoration; gene therapy; healing; histone modification; human old age (65+); human tissue; improved functioning; in vivo; keratinocyte; melanoma; member; methylome; mouse model; multiplexed imaging; novel; novel strategies; regeneration potential; regenerative; response; retinal neuron; scaffold; skin disorder; skin regeneration; stem; stem cell aging; stem cell biology; stem cell function; stem cells; synergism; therapeutic evaluation; transcriptome; translational approach; translocase; wound healing

SUMMARY Defective wound healing accounts for enormous morbidity and fiscal burden worldwide. Chronological aging of skin is at the foundation of defective wound healing, although little is known regarding the underlying cause of this association. However compelling data indicates that skin stem cells that become deficient as we age are the basis for defective wound healing. Moreover, reversible epigenetic regulation plays a critical role in stem cell health and maintenance. We therefore posit that the fundamental underpinnings of regenerative healing of skin reside in the epigenetic regulation of skin stem cells. Here, we propose to study epigenetic changes in skin regeneration in wound healing and aging, and test a newly discovered form of in vivo epigenetic reprogramming that we predict will reverse the age and restore function to aging stem cells. Thus, the primary goal of this project is to elucidate epigenetic mechanisms of skin stem cell regulation with focus on DNA methylation/hydroxymethylation and histone modification, and to develop novel and practical translational approaches to reprogramming age-related stem cell epigenetic aberrances. We have assembled a synergistic interdisciplinary team of investigators with a history of pioneering discovery in the areas of aging biology, epigenetics, epigenetic reprogramming, skin stem cell biology, dermatopathology and biomarker application. We also have developed experimental models that encompass biodegradable wound healing scaffold development, human skin xenotransplantation, three-dimensional bioprinting, and a mouse model of epigenetically inducible premature aging. Thus, we will leverage multiple points of synergy, experience, and collaborative interaction to tackle the complex and clinically important questions of age-related wound healing deficiency. Most importantly, we will define and test the therapeutic effects of epigenetic reprogramming in our novel and complementary pre-clinical model systems. This proposal presents a new approach of epigenetic reprogramming of functionally deficient aging stem cells to enhance skin regeneration in order to heal chronic wounds in the aging populace. If successful, such an approach could transform the way we think about the aging process and treating age-related skin disorders.

概括 伤口愈合不良在全世界造成巨大的发病率和财政负担。按时间老化 皮肤是伤口愈合不良的基础，尽管人们对伤口愈合不良的根本原因知之甚少。 这个协会。然而令人信服的数据表明，随着年龄的增长而变得缺乏的皮肤干细胞是 伤口愈合不良的基础。此外，可逆表观遗传调控在干细胞中发挥着关键作用 健康和维护。因此，我们认为皮肤再生愈合的基本基础 存在于皮肤干细胞的表观遗传调控中。在这里，我们建议研究皮肤的表观遗传变化 伤口愈合和衰老中的再生，并测试新发现的体内表观遗传形式 我们预测重编程将逆转衰老并恢复衰老干细胞的功能。因此， 该项目的主要目标是重点阐明皮肤干细胞调节的表观遗传机制 DNA甲基化/羟甲基化和组蛋白修饰的研究，并开发新颖实用的 重编程与年龄相关的干细胞表观遗传异常的转化方法。我们有 组建了一支具有协同作用的跨学科研究团队，在该领域具有开创性发现的历史 衰老生物学、表观遗传学、表观遗传重编程、皮肤干细胞生物学、皮肤病理学和 生物标志物应用。我们还开发了包含可生物降解伤口的实验模型 愈合支架开发、人类皮肤异种移植、三维生物打印和小鼠 表观遗传诱导的过早衰老模型。因此，我们将利用多个协同点、经验、 和协作互动，以解决与年龄相关的伤口愈合的复杂且临床上重要的问题 不足。最重要的是，我们将在我们的研究中定义并测试表观遗传重编程的治疗效果。 新颖且互补的临床前模型系统。该提案提出了一种新的表观遗传学方法 对功能缺陷的衰老干细胞进行重新编程，以增强皮肤再生，从而治愈慢性病 老年人的伤口。如果成功的话，这种方法可能会改变我们对老龄化的看法 处理和治疗与年龄相关的皮肤疾病。