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 在成人中，皮肤不断地自我更新，皮肤的基底层干细胞(EPSCs) 毛囊间上皮和毛囊隆起中的毛囊干细胞(Hfscs)起作用。 用于维持损伤后的组织完整性、结构和再上皮化。然而，在生物体的 这些成年皮肤的SC池要么失去活力，要么数量减少，表现为衰老- 相关表型包括表皮萎缩、脆弱、脱发障碍和伤口愈合延迟。这个 导致成人皮肤SC老化的基本机制仍然很大程度上是未知的。 到目前为止，对无脊椎动物和衰老细胞模型的研究表明，全球 许多组蛋白甲基化的占有率以及甲基转移酶和去甲基酶的调节增加 生物长寿。虽然大多数这些研究都为我们理解表观遗传学 机制影响衰老过程，如果这些机制也起作用，就需要加以解决 哺乳动物组织的衰老。我的初步体内功能丧失研究表明，保守的 表观遗传调节因子多梳抑制复合体(Prc)可能在hfSCs中发挥不同的作用。 和EPSCs，以维持其在成人皮肤中的寿命。这一点特别耐人寻味，因为 全基因组研究表明，老年hfscs染色质可及性的调节建立了 促进衰老的转录景观。这项提议目的是增加这些相关的 观察并阐明表观遗传调节因子及其相应的组蛋白修饰是否具有 在保护皮肤SC长寿方面的功能作用。为此目的，该提案的具体目标力求 将体内功能性遗传模型与最先进的多重组学方法相结合，以： 1)描述不同SC的转录和染色质景观随年龄的变化 成人皮肤的池塘； 2)测试多梳依赖机制在维持长寿和再生方面的功能作用 成人皮肤干细胞的能力；以及 3)建立与年龄相关的SC染色质状态变化促进衰老的功能关联 相关表型。 这一建议的结果将显著增强我们对年龄相关性变化的理解 表观遗传机制建立了促进SC老化的转录图景，并将提供新的 翻译研究在衰老相关疾病治疗中的应用的科学途径 精神错乱。