Posttranscriptional control of epidermal progenitors senescence

总结/摘要 成人器官通过严格调节的增殖、分化 以及在正常组织稳态或组织修复期间干细胞的自我更新。近几 年复层鳞状上皮，如表皮，其高度的周转和 承受可能是最高数量的伤害的能力已经成为“黄金标准”， 祖细胞稳态模型。毛囊间表皮的基底层由 罕见的静止和更普遍的活跃循环干细胞和祖细胞。增殖 基底角质形成细胞负责恒定的组织再生，其特征在于 代谢增加，同时阻止分化。在同一 同时，需要保护活跃循环的干细胞和祖细胞免受 正在经历与其强烈增殖状态相关的衰老。因此，主 本申请的重点是阐明防止衰老的分子途径 在稳态过程中增殖表皮祖细胞的表型， 损伤驱动的组织再生在我们最近发表的工作和初步研究中， 应用一种无偏见的，系统的方法来捕获表皮细胞的mRNA结合蛋白， YBX 1（Y-box binding protein-1，YBX 1）是一种重要的前体细胞效应子， 功能YBX 1的表达仅限于循环表皮祖细胞及其遗传学意义 消融导致表皮结构的缺陷。我们发现YBX 1 通过调节一个转录因子的翻译来负性地控制表皮祖细胞的衰老。 衰老相关的细胞因子mRNA亚群通过其3'非翻译区（UTR）。我们 现在正在研究YBX 1驱动表皮细胞的分子机制， 缺陷，并测试假设，YBX 1在表皮中的失调 促进改变稳态和损伤诱导再生。我们将定义 YBX 1驱动的衰老相关细胞因子调节机制，其生物学特性 角化细胞祖细胞功能和执行细胞命运决定的能力的重要性。 总之，这些研究定位于确定一种新的预防相关控制水平 衰老和细胞因子的产生在体外和体内的表皮。

Summary/Abstract Adult organs are maintained through a tightly regulated balance of proliferation, differentiation, and self-renewal of stem cells, during normal tissue homeostasis or tissue repair. In recent years stratified squamous epithelia such as the epidermis with its high degree of turnover and ability to withstand perhaps the highest number of injuries have become the “gold standard” for models of progenitor cell homeostasis. The basal layer of the interfollicular epidermis consists of rare quiescent and more prevalent actively cycling stem and progenitor cells. The proliferating basal keratinocytes are responsible for constant tissue regeneration and are characterized by increased metabolism coupled with prevention of commitment to differentiation. At the same time, the actively cycling stem and progenitor cells need to be protected from the risk of undergoing senescence associated with their intense proliferative state. Therefore, the main focus of this application is to elucidate the molecular pathways preventing senescence phenotypes in proliferating epidermal progenitor cells during steady state homeostasis and damage-driven tissue regeneration. In our recently published work and preliminary studies we applied an unbiased, systematic approach to capture the mRNA binding proteins of epidermal progenitors and identified YBX1 (Y-box binding protein-1) as a critical effector of progenitor function. YBX1 expression is restricted to the cycling epidermal progenitors and its genetic ablation leads to defects in in the architecture of the epidermis. We uncovered that YBX1 negatively controls epidermal progenitor senescence by regulating the translation of a senescence-associated subset of cytokine mRNAs via their 3’ untranslated regions (UTRs). We are now proposing to investigate the molecular mechanisms of the YBX1 driven epidermal deficiencies and also to test the hypothesis that dysregulation of YBX1 in the epidermis promotes altered homeostatic and injury-induced regeneration. We will define the biochemical machinery underlying YBX1 driven regulation of senescence-associated cytokines, its biological significance for keratinocyte progenitor function and ability to execute cell fate decisions. Together, these studies are positioned to identify a novel level of translation-associated control of senescence and cytokine production in the epidermis in vitro and in vivo.