Metabolic Reprogramming and Regeneration in the Aged Epidermis

老化表皮的代谢重编程和再生

• 批准号: 10494658
• 负责人: Anna Mandinova
• 金额: $ 47.46万
• 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/10494658
• 关键词: Acetyl-CoA Carboxylase; Address; Adult; Affect; Age; Aging; Animal Model; Aptitude; Artificial Organs; Artificial skin; Automobile Driving; Candidate Disease Gene; Carnitine Palmitoyltransferase I; Cell Aging; Cells; Chromatin Structure; Chronology; Coenzyme A-Transferases; Complex; Data; Defect; Dermal; Deterioration; Development; Elderly; Enzymes; Epidermis; Epigenetic Process; Equilibrium; Esthesia; Excretory function; Failure; Gases; Genes; Genetic Transcription; Glycolysis; Homeostasis; Human; Human body; Impairment; Impotence; In Situ; In Vitro; Injections; Keto Acids; Longevity; Mesenchymal Stem Cells; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Mus; Natural regeneration; Organ; Organism; Oxidative Phosphorylation; Phenotype; Physiological; Population; Process; Regenerative capacity; Regenerative response; Regulation; Resistance; Respiration; Role; Skin; Skin Aging; Skin injury; Skin wound healing; Structure; System; Technology; Testing; Thick; Tissues; Transcription Alteration; Water; absorption; age related; aged; base; epidermal stem cell; exhaustion; fatty acid oxidation; gene function; in utero; in vivo; keratinocyte; knock-down; knockout gene; lipid metabolism; loss of function; metabolomics; mouse model; novel; overexpression; progenitor; repository; response; response to injury; self-renewal; skin barrier; skin regeneration; stem; stem cell aging; stem cell population; stem cells; succinyl-coenzyme A; theories; tissue regeneration; transcriptome; transcriptome sequencing; ultrasound; wound healing

SUMMARY Human skin is the largest and one of the most complex organs in the human body. It performs diverse functions, ranging from protection, sensation, heat regulation, absorption of gases, excretion of sweat, and water resistance. Skin structure and functions gradually deteriorate with age. While there is a substantial effort towards understanding cellular mechanisms that cause cellular aging and influence the lifespan of model organisms, the molecular mechanisms of age-related alterations in human skin in vivo are barely explored. The limited number of studies on this subject conducted by bulk sequencing or metabolomics analyses of whole tissue lysates failed to provide evidence on robust transcriptional, epigenetic or metabolic alterations that drive skin aging or generate any reliable theory on the molecular determinates of these processes. We hypothesize that aging in the human epidermis affects only the discrete populations of cells with stem and progenitor features and results in the deterioration of their ability to drive self-renewal. Our preliminary data show that cycling stem cells maintain epidermal homeostasis by undergoing a profound metabolic reprograming, which determines their ability to differentiate and build the cornified barrier. We also found that the aptitude to initiate such metabolic adaptations is progressively impaired in aging stem cells, which correlates with decreased expression of certain metabolic enzymes. Consequently, we propose that exhaustion of metabolic reprogramming capacity is caused by aging of the epidermal stem cells and is highly relevant for age-related alterations in the skin. We plan in aim 1 to utilize our unique repository of primary human epidermal stem cells derived from donors of different ages and further expose the metabolic failure of elderly progenitors. We will define the transcriptional alterations underlying the defects in reprogramming from cytosolic glycolysis to mitochondrial oxidative phosphorylation. Aim two will employ human artificial skin equivalents and a recently developed total thickness human skin regeneration system as models of epidermal homeostasis and wound healing to address the functional significance of altered metabolism-associated genes identified in Aim 1. Based on these findings, we will further explore the function of the gene candidates in vivo in the mouse epidermis (in aim 3) using a highly efficient in utero gene-editing system.

总结 人体皮肤是人体最大、最复杂的器官之一。它执行多种功能， 从保护、感觉、热调节、气体吸收、汗液和水的排泄 阻力皮肤的结构和功能随着年龄的增长而逐渐退化。虽然有很大的努力， 了解导致细胞衰老和影响模型生物寿命的细胞机制， 在人体皮肤中与年龄相关的改变的分子机制几乎没有被探索。数量有限 通过对整个组织裂解物进行批量测序或代谢组学分析进行的关于该主题的研究失败 提供证据证明，强大的转录，表观遗传或代谢改变，驱动皮肤老化或产生 关于这些过程的分子决定因素的任何可靠理论。我们假设人类的衰老 表皮仅影响具有干细胞和祖细胞特征的离散细胞群， 他们自我更新能力的下降。我们的初步数据显示， 表皮稳态通过经历深刻的代谢重编程，这决定了他们的能力， 差异化，构建生态屏障。我们还发现启动这种代谢适应的能力 在衰老干细胞中进行性受损，这与某些代谢产物的表达减少有关。 内切酶因此，我们认为代谢重编程能力的衰竭是由衰老引起的 表皮干细胞的生长和与年龄相关的皮肤变化高度相关。我们在目标1中计划 利用我们独特的来源于不同年龄供体的原代人表皮干细胞库， 进一步暴露了老年祖细胞的代谢衰竭。我们将定义潜在的转录改变 从胞质糖酵解到线粒体氧化磷酸化的重编程缺陷。瞄准二号意志 采用人类人造皮肤等效物和最近开发的全厚度人类皮肤再生 系统作为表皮稳态和伤口愈合的模型，以解决改变的 Aim 1中鉴定的代谢相关基因。基于这些发现，我们将进一步探讨 使用高效的子宫内基因编辑，在小鼠表皮中的体内基因候选物（在aim 3中） 系统