Multicomponent Therapy for Age-related Skin Stem Cell Deficiency

治疗与年龄相关的皮肤干细胞缺乏症的多成分疗法

• 批准号: 10494654
• 负责人: Markus H. Frank
• 金额: $ 235.16万
• 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/10494654
• 关键词: Address; Affect; Age; Aging; Animals; Appearance; Atrophic; Bioinformatics; Biology; COVID-19; Cell Communication; Cells; Cellular Metabolic Process; Chronic; Clinical; Cutaneous; DNA; Data; Defect; Dermal; Detection; Development; Elderly; Epidemic; Epigenetic Process; Evaluation; Evolution; Functional disorder; Generations; Genomics; Goals; Health; Human; Human Resources; Individual; Institution; Left; Maintenance; Maps; Membrane Transport Proteins; Metabolic; Methods; Natural regeneration; Normal tissue morphology; Pathology; Pathway interactions; Phenotype; Physiological; Population; Premature aging syndrome; Prevention; Productivity; Receptor Cell; Records; Regenerative response; Regulation; Research; Research Personnel; Research Proposals; Resources; Role; Severities; Skin; Skin injury; Societies; Source; Stem cell pluripotency; Technology; Therapeutic; Thinness; United States; Youth; age related; aged; authority; base; biomarker discovery; chronic ulcer; combinatorial; comorbidity; decubitus ulcer; design; editorial; epidermal stem cell; epigenomics; healing; health care service utilization; in vivo; metabolomics; middle age; mouse model; multidisciplinary; neglect; novel; novel strategies; pluripotency; psychosocial; receptor; regeneration potential; regenerative; regenerative cell; repaired; response; restoration; skin damage; skin ulcer; skin wound; stem; stem cell biology; stem cell fate; stem cell function; stem cells; success; synergism; targeted treatment; therapeutic target; tissue injury; tissue repair; wound; wound healing; wound treatment

SUMMARY Chronic ulcers, defined as wounds that fail to heal within a three-month period, are associated with age-related dysfunction in skin stem cells that not only has potential to blunt tissue repair, but also accounts for skin fragility, atrophy, and the "aging phenotype" that itself has clinical as well as psychosocial implications. Non-healing ulcers in aging individuals represent a multibillion dollar burden in the United States and to society globally, both through utilization of health care resources as well as through reduction in productivity. Nonetheless, it is recognized that "the basic biology and the influence of age-associated changes on wound healing are poorly understood, and there are numerous research questions still to be answered". To address this important issue, we have 1) assembled a highly collaborative and multidisciplinary team of investigators with established track records in skin pathology, regenerative and stem cell biology, wound healing, bioinformatics, and the pathobiology of aging; 2) leveraged the resources of seven Harvard Institutions to develop a unified and state- of-the-art approach to decipher the role skin stem cell deficiency in age-related defective wound healing; and 3) generated data-based hypotheses and identified inter-project synergies that will maximize productivity and translational focus. Our fundamental hypothesis is that identification and interrogation of three major, inter- related, and therapeutically targetable/reprogrammable pathways relevant to age-related skin stem cell dysfunction, a) metabolic, b) epigenetic, and c) membrane transporter/receptor, will pave the way for combinatorial (multicomponent) therapies necessary for more robust healing and regenerative responses to skin injury. We will pursue this goal through six strategies that have been developed by the key personnel of this PPG: 1) discovery of biomarkers for epidermal and dermal stem cell identification and manipulation; 2) determination of metabolic regulators required for epidermal progenitor activity and maintenance; 3) identification of novel epigenetic pathways that govern skin stem cell function and vitality; 4) development and evaluation of unique murine models that permit study of human wound healing in vivo; 5) deployment of lineage tracking technologies that facilitate detection of experimentally-manipulated stem cell fate in healing wounds; and 6) generation of new animal strains and for epigenomic induction of premature aging and methods for genomic restoration of stem cell youth and pluripotency. Our overall aims seek to answer the following questions: 1) How can one map the key metabolomic, epigenetic, and cell receptor stem cell pathways that drive age-related wound healing dysfunction?; 2) What are the therapeutically-accessible nodes for stem cell-directed multicomponent combinatorial targeting within these pathways?; and 3) What are the agents that likely will affect restoration of robust and regenerative stem cell-driven responses to wound healing and support physiologic cutaneous maintenance and health? Success in this endeavor could be transformative in understanding how aged stem cells may be restored to functional vigor implicit to normal tissue integrity and regenerative potential.

概括 慢性溃疡，定义为三个月内无法愈合的伤口，与年龄有关 皮肤干细胞功能障碍不仅有可能削弱组织修复，而且还会导致皮肤脆弱， 萎缩和“衰老表型”本身具有临床和社会心理影响。不愈合 老年人的溃疡给美国和全球社会带来了数十亿美元的负担 通过利用医疗保健资源以及降低生产力。尽管如此，它是 认识到“基础生物学和与年龄相关的变化对伤口愈合的影响尚不清楚 理解，并且还有许多研究问题有待回答”。为了解决这个重要问题， 我们 1) 组建了一支高度协作、多学科的研究团队，具有既定的跟踪 皮肤病理学、再生和干细胞生物学、伤口愈合、生物信息学和 衰老病理学； 2）利用哈佛七个机构的资源，开发一个统一的、国家级的 最先进的方法破译皮肤干细胞缺乏在与年龄相关的伤口愈合缺陷中的作用；和 3) 生成基于数据的假设并确定项目间的协同作用，从而最大限度地提高生产力和 翻译焦点。我们的基本假设是，识别和询问三个主要的、 与年龄相关的皮肤干细胞相关的、治疗上可靶向/可重编程的途径 功能障碍，a）代谢，b）表观遗传，c）膜转运蛋白/受体，将为 组合（多成分）疗法是更强大的皮肤愈合和再生反应所必需的 受伤。我们将通过该中心关键人员制定的六项战略来实现这一目标 PPG：1）发现用于表皮和真皮干细胞识别和操作的生物标志物； 2） 确定表皮祖细胞活性和维持所需的代谢调节剂； 3）鉴定 控制皮肤干细胞功能和活力的新型表观遗传途径； 4）开发和评估 独特的小鼠模型，可以研究人体伤口愈合的体内情况； 5) 血统追踪的部署 有助于检测实验操纵的干细胞在伤口愈合过程中的命运的技术；和 6) 新动物品系的产生和过早衰老的表观基因组诱导以及基因组方法 恢复干细胞年轻和多能性。我们的总体目标旨在回答以下问题：1）如何 能否绘制出驱动年龄相关伤口的关键代谢组学、表观遗传和细胞受体干细胞通路 治愈功能障碍？ 2) 干细胞定向多组分治疗可及的节点有哪些 这些途径内的组合靶向？ 3) 哪些因素可能会影响恢复 强大的再生干细胞驱动的伤口愈合反应并支持生理皮肤 保养和健康？这项努力的成功可能会变革性地理解衰老是如何发生的 细胞可以恢复正常组织完整性和再生潜力所隐含的功能活力。