Multicomponent Therapy for Age-related Skin Stem Cell Deficiency

总结 慢性溃疡，定义为伤口在三个月内未能愈合，与年龄相关的 皮肤干细胞的功能障碍不仅有可能使组织修复变钝，而且还导致皮肤脆弱， 萎缩，以及本身具有临床和心理社会影响的"衰老表型"。不愈合 老年人的溃疡在美国和全球社会都是数十亿美元的负担， 通过利用卫生保健资源以及通过降低生产率。尽管如此， 认识到"基础生物学和年龄相关变化对伤口愈合的影响很差， 我们已经了解，还有许多研究问题有待回答"。为了解决这一重要问题， 我们已经1）组建了一个高度合作和多学科的调查团队， 记录在皮肤病理学，再生和干细胞生物学，伤口愈合，生物信息学， 衰老的病理生物学; 2）利用七个哈佛机构的资源来开发一个统一的国家- 最先进的方法来破译皮肤干细胞缺乏在年龄相关的缺陷性伤口愈合中的作用;以及3） 产生了基于数据的假设，并确定了将最大限度地提高生产力的项目间协同作用， 翻译焦点我们的基本假设是，识别和审讯三个主要的，相互- 与年龄相关的皮肤干细胞相关的治疗靶向/可重编程途径 功能障碍，a）代谢，B）表观遗传，和c）膜转运蛋白/受体，将铺平道路 组合（多组分）疗法对于皮肤更稳健的愈合和再生反应是必要的 损伤我们将通过六项战略来实现这一目标，这些战略是由本组织的主要人员制定的。 PPG：1）发现用于表皮和真皮干细胞鉴定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 允许在体内研究人类伤口愈合的独特鼠模型; 5）谱系追踪的部署 促进检测愈合伤口中实验操作的干细胞命运的技术;以及6） 产生新的动物品系和用于表观基因组诱导过早衰老的方法 恢复干细胞年轻和多能性。我们的总体目标是寻求回答以下问题：1）如何 能否绘制出导致年龄相关创伤的关键代谢组学、表观遗传学和细胞受体干细胞通路 愈合功能障碍？2)干细胞定向多组分治疗的可及节点是什么？ 在这些通路中的组合靶向？和3）哪些因素可能会影响恢复 强大的和再生的干细胞驱动的反应，伤口愈合和支持生理皮肤 维护和健康？这项努力的成功可能会改变人们对老化干细胞 细胞可以恢复到正常组织完整性和再生潜力所隐含的功能活力。

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.