Posttranscriptional control of epidermal progenitors senescence

摘要/摘要 成年器官通过严格调控的增殖、分化、 干细胞在正常组织动态平衡或组织修复期间的自我更新。在最近 多年复层的鳞状上皮，如表皮，具有高度的周转和 能够承受也许是最高数量的伤害已经成为 祖细胞动态平衡模型。毛囊间表皮的基底层由 罕见的静止和更普遍的活跃循环的干细胞和祖细胞。不断扩散的 基底角质形成细胞负责持续的组织再生，其特征是 新陈代谢增加，同时防止对分化的承诺。同时 随着时间的推移，活跃的循环干细胞和祖细胞需要受到保护，以避免 经历着与其强烈的增殖状态相关的衰老。因此，主要的 这一应用的重点是阐明防止衰老的分子途径 稳态和稳态状态下增殖的表皮祖细胞的表型 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，我们 应用一种无偏的、系统的方法来获取表皮的mRNA结合蛋白 YBX1(Y盒结合蛋白-1)是祖细胞的关键效应因子 功能。YBX1的表达仅限于周期表皮祖细胞及其基因 消融会导致表皮结构的缺陷。我们发现了YBX1 通过调节A基因的翻译负向控制表皮祖细胞的衰老 细胞因子3‘非翻译区(UTRs)中与衰老相关的mRNAs子集。我们 现在正在提议研究YBX1驱动的表皮的分子机制 也是为了验证YBX1在表皮中的调节失调的假设 促进动态平衡改变和损伤诱导的再生。我们将定义生物化学 YBX1调控衰老相关细胞因子的机制及其生物学意义 角质形成细胞前体功能和执行细胞命运决定能力的意义。 总之，这些研究旨在确定与翻译相关的控制的新水平 在体外和体内的表皮衰老和细胞因子产生的研究。

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.