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Posttranscriptional control of epidermal progenitors senescence

表皮祖细胞衰老的转录后控制

基本信息

批准号：
10582626
负责人：
Ya-Chieh Hsu
金额：
$ 36.46万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10582626
关键词：
3&apos Untranslated Regions Ablation Acute Adult Affect Aging Anabolism Architecture Artificial Organs Binding Binding Proteins Biochemical Biological CXCL1 gene CXCL2 gene Cell Aging Cell Death Cell Lineage Cells Coupled Cytokine Signaling DNA binding protein B Data Defect Development Epidermis Epigenetic Process Epithelium Equilibrium Genetic Genetic Transcription Guide RNA Homeostasis Human Human body IL24 gene IL8 gene Impairment In Vitro Injections Injury Intervention Laboratories Lentivirus Mediating Messenger RNA Metabolism Modality Modeling Molecular Mus Natural regeneration Nature Normal tissue morphology Organ Organ Model PIK3CG gene PTGS2 gene Pathway interactions Phenotype Phosphorylation Phosphotransferases Population Positioning Attribute Post-Transcriptional Regulation Post-Translational Protein Processing Prevention Process Production Proliferating Proteins Proteome Publishing Regenerative response Regulation Ribosomes Risk Role Signal Pathway Skin Skin injury Skin wound healing Stratified Squamous Epithelium Stratum Basale Stress Testing Therapeutic Intervention Thick Time Tissues Translations Work acute wound cytokine epidermal stem cell in utero in vivo insight keratinocyte loss of function novel novel therapeutic intervention pharmacologic posttranscriptional preservation prevent progenitor regeneration potential response response to injury self-renewal senescence skin disorder skin regeneration stem stem cell division stem cell function stem cell homeostasis stem cell self renewal stem cells tissue regeneration tissue repair wound healing

项目摘要

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.

摘要/文摘