Identifying epigenetic factors in control of epidermal stem cell longevity in the adult skin

识别控制成人皮肤表皮干细胞寿命的表观遗传因素

• 批准号: 10723212
• 负责人: Pooja Flora
• 金额: $ 10.62万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723212
• 关键词: Address; Adult; Age; Aging; Architecture; Atrophic; Automobile Driving; Biochemical; Cell Count; Cell model; Chromatin; Code; Complex; Control Animal; Curiosities; Cutaneous; Disease; Epidermis; Epigenetic Process; Epithelium; Equilibrium; Failure; Foundations; Future; Genetic Models; Genetic Transcription; Genetic study; Goals; Growth; Hair; Hair follicle structure; Homeostasis; Human; Immunofluorescence Immunologic; Impaired wound healing; In Vitro; Injury; Intrinsic factor; Invertebrates; Knowledge; Light; Longevity; Malignant Neoplasms; Mediating; Methods; Methyltransferase; Molecular; Mus; Organism; PRC1 Protein; Phase; Phenotype; Polycomb; Process; Regenerative capacity; Regulation; Regulator Genes; Repression; Research; Research Personnel; Role; Running; Skin; Skin Aging; Stratified Epithelium; Stratum Basale; Structure; Testing; Thinness; Tissues; Translational Research; Work; age related; aged; base; cell age; cell community; cell type; epidermal stem cell; epigenetic regulation; exhaustion; gene repression; genome-wide analysis; histone methylation; histone modification; in vivo; insight; loss of function; multiple omics; novel; premature; preservation; programs; regeneration potential; self-renewal; senescence; stem cell aging; stem cell differentiation; stem cell self renewal; stem cells; wound healing

Project Summary In adults, the skin constantly renews itself and the stem cells (SCs) of the basal layer (EpSCs) of the interfollicular epithelium and the hair follicle stem cells (HFSCs) residing in the hair follicle bulge are responsible for maintaining tissue integrity, structure, and reepithelization following an injury. However, over an organism’s lifetime these SC pools of the adult skin either lose their vigor or diminish in numbers which manifests into aging- related phenotypes that include epidermal atrophy, fragility, hair loss disorders and delayed wound healing. The fundamental mechanisms that drive SC aging in the adult skin remain largely unknown. To date research in invertebrate and cellular models of aging have shown that there is a change in global occupancy of many histone methylations, and modulation of methyltransferases and demethylases increase organism longevity. While most of these studies have paved the way for us to understand how epigenetic mechanisms influence the aging process, there is a need for addressing if these mechanisms also contribute towards aging of a mammalian tissue. My preliminary in vivo loss-of-function studies indicate that the conserved epigenetic regulators, Polycomb repressive complexes (PRCs), may be functioning differentially in the HFSCs and EpSCs to maintain their longevity in the adult skin. This is particularly intriguing in light of the fact that genome-wide studies have implicated that the modulation of chromatin accessibility in aged HFSCs establish a transcriptional landscape that promotes aging. The goal of this proposal is to add to these correlative observations and elucidate if epigenetic regulators and their corresponding histone modifications have a functional role in safeguarding SC longevity in the skin. To this end, the Specific Aims of this Proposal seek to combine functional in vivo genetic models with state-of-the-art multi-omics approaches to: 1) Characterize the age-dependent changes in transcriptional and chromatin landscape of the various SC pools of the adult skin; 2) Test the functional role of Polycomb-dependent mechanisms in maintaining the longevity and regenerative capacity of adult skin SCs; and 3) Establish a functional correlation that age-dependent changes in the SC chromatin state promotes aging- associated phenotypes. The results of this Proposal will significantly enhance our understanding of how age-dependent changes in epigenetic mechanisms establish a transcriptional landscape that promotes SC aging and will provide new scientific avenues for translational research application in the treatment for aging-associated conditions and disorders.

项目摘要 在成年人中，皮肤不断更新本身和基本层（EPSC）的干细胞（SC） 毛囊凸起的毛囊上皮和毛囊干细胞（HFSC）是负责 用于维持损伤后组织完整性，结构和再填充。但是，在有机体上 终生这些成人皮肤的SC池要么失去活力或减少的数量，表现为衰老 相关的表型，包括表皮萎缩，脆弱性，脱发障碍和伤口延迟愈合。 驱动成人皮肤中SC衰老的基本机制在很大程度上是未知的。 迄今为止在衰老的无脊椎动物和细胞模型中的研究表明，全球有变化 许多组蛋白甲基化的占用，甲基转移酶和去甲基酶的调节增加 生物寿命。尽管这些研究大多数为我们了解表观遗传的道路铺平了道路 机制影响衰老过程，需要解决这些机制是否也有助于 朝着哺乳动物组织衰老。我的初步体内功能丧失研究表明，保守的 表观遗传调节剂PolyComb反射复合物（PRC）在HFSC中的功能可能不同 EPSC在成人皮肤中保持寿命。鉴于这一事实，这尤其引人入胜 全基因组的研究已经实施了，老年HFSC的染色质可及性的调节建立了 促进衰老的转录格局。该建议的目的是增加这些相关性 观察和阐明表观遗传调节剂及其相应组蛋白的修饰是否具有 在保护皮肤中的SC寿命方面的功能作用。为此，该提案的具体目标寻求 将功能性在体内遗传模型与最先进的多摩学方法相结合： 1）表征各种SC的转录和染色质景观的年龄变化 成人皮肤的池； 2）测试依赖多孔的机制在保持寿命和再生中的功能作用 成人皮肤SC的能力；和 3）建立功能相关性，即SC染色质状态年龄依赖性变化会促进衰老 - 相关表型。 该提案的结果将大大增强我们对年龄依赖性变化的理解 表观遗传机制建立了一种转录景观，可促进SC衰老并提供新的 在衰老相关状况和 疾病。