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：
10359741
负责人：
Ya-Chieh Hsu
金额：
$ 36.1万
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359741
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 Epithelial Equilibrium Genetic Genetic Transcription Gold Guide RNA Homeostasis Human Human body 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 PTGS2 gene Pathway interactions Pharmacology 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 human model in utero in vivo insight keratinocyte loss of function novel novel therapeutic intervention preservation prevent progenitor regeneration potential response response to injury self-renewal senescence skin disorder skin regeneration 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/摘要成体器官通过严格调节增殖、分化、以及干细胞在正常组织稳态或组织修复过程中的自我更新。年复层鳞状上皮，如表皮，其周转程度高，承受最多伤害的能力已经成为了“黄金标准” 祖细胞稳态模型滤泡间表皮的基底层由以下部分组成。罕见的静止细胞和更普遍的活跃循环干细胞和祖细胞。角质形成细胞负责持续的组织再生，其特点是增加新陈代谢，同时防止分化。此时，需要保护活跃循环的干细胞和祖细胞免受以下风险：因此，衰老与它们的强烈增殖状态有关。该应用的重点是阐明预防衰老的分子途径稳态稳态期间增殖的表皮祖细胞的表型和在我们最近发表的工作和初步研究中，我们研究了损伤驱动的组织再生。应用公正、系统的方法来捕获表皮的 mRNA 结合蛋白并鉴定出 YBX1（Y-box 结合蛋白-1）是祖细胞的关键效应子 YBX1 的表达仅限于循环表皮祖细胞及其遗传。我们发现 YBX1 消融会导致表皮结构缺陷。通过调节a的翻译来负控制表皮祖细胞衰老细胞因子 mRNA 的衰老相关子集通过其 3' 非翻译区（UTR）。现在提议研究 YBX1 驱动的表皮的分子机制缺陷并检验表皮中 YBX1 失调的假设促进改变的稳态和损伤诱导的再生。我们将定义生化。 YBX1 驱动衰老相关细胞因子调节的机制及其生物学对角质形成细胞祖细胞功能和执行细胞命运决定的能力具有重要意义。总之，这些研究旨在确定翻译相关控制的新水平体外和体内表皮衰老和细胞因子产生的影响。