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.