Regulation of Human Epidermal Tumorigenesis by the mRNA Degradation Pathway

mRNA 降解途径调控人表皮肿瘤发生

基本信息

批准号：
10304861
负责人：
GEORGE L SEN
金额：
$ 39.21万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304861
关键词：
3-Dimensional 5&apos -exoribonuclease Address Apoptosis Basal cell carcinoma Basement membrane Binding Cell Adhesion Cell Compartmentation Cell Polarity Cells Code Complex Data Degradation Pathway Dermal Development Differentiation and Growth Disease Epidermis Epithelial Equilibrium Foundations Generations Genetic Transcription Growth Homeostasis Human Immune Lead Malignant Neoplasms Mediating Messenger RNA Modeling Molecular Mus Natural regeneration Neoplasms Play Population Process Proteins Psoriasis Publications Publishing RNA Regulation Research Design Role Skin Squamous cell carcinoma Stratum Basale Structure Tissues Transcript Tumor stage Water Work cancer site chronic wound clinically relevant crosslinking and immunoprecipitation sequencing design epidermal stem cell exosome experimental study human model insight knock-down loss of function mRNA Transcript Degradation neoplastic novel strategies overexpression premature prevent prototype self-renewal skin disorder stem cells therapy development transcription factor tumor tumor growth tumor initiation tumor progression tumorigenesis

项目摘要

Project Summary/Abstract Background: Transcriptional mechanisms that regulate epidermal homeostasis and neoplasia have been well established but recently we have discovered that post- transcriptional mechanisms play prominent roles in maintaining epidermal self-renewal. We have shown that the 3'-5' mRNA degradation pathway mediated by the exosome complex is necessary to maintain epidermal self-renewal. Specifically, the exosome subunits, EXOSC7, EXOSC9, and EXSCO10 are necessary to prevent premature differentiation of epidermal stem cells by targeting and degrading transcripts that code for potent pro-differentiation transcription factors. Objective/hypothesis: This proposal seeks to understand the molecular mechanisms governing the progression from normal to neoplastic skin using a RAS driven human epidermal tumor model. Our preliminary data suggests that a 5 subunit exosome subcomplex is upregulated during tumor initiation and targets/degrades transcripts coding for factors that would inhibit tumor growth and survival. Our objective is to characterize the role of each tumor induced exosome subunit in the progression of normal to neoplastic skin. Furthermore we seek to determine the specific transcripts that each exosome subunit binds during tumor initiation to promote tumorigenesis. Specific Aims: (1) To determine the role of exosome subunits on the progression from normal to neoplastic skin and (2) to identify and characterize the transcripts associated with exosome subunits. Study Design: To study epidermal homeostasis in a more clinically relevant setting, we generate 3-dimensionally intact human skin, containing human epidermal cells (that have been permanently knocked down for exosome subunits) in the context of human dermal stroma and basement membrane, regenerated on immune compromised mice. By using this model, we can perform loss of function experiments on exosome subunits in regenerated human skin to characterize their role in epidermal growth, differentiation, and progression to neoplasia. We will use CLIP-Seq to determine the RNAs associated with the exosome subunits during the progression from normal to neoplastic epidermis.

项目概要/摘要背景：调节表皮稳态的转录机制肿瘤形成已经很确定，但最近我们发现，术后转录机制在维持表皮自我更新中发挥着重要作用。我们已经证明外泌体介导的 3'-5' mRNA 降解途径复合物是维持表皮自我更新所必需的。具体而言，外泌体亚基 EXOSC7、EXOSC9 和 EXSCO10 对于防止早产是必要的通过靶向和降解编码的转录本来分化表皮干细胞有效的促分化转录因子。目标/假设：该提案旨在了解分子机制使用 RAS 驱动的人类来控制从正常皮肤到肿瘤皮肤的进展表皮肿瘤模型。我们的初步数据表明，5 个亚基的外泌体亚复合物在肿瘤发生过程中上调并靶向/降解转录本编码抑制肿瘤生长和存活的因素。我们的目标是描述每个肿瘤诱导的外泌体亚基在肿瘤进展中的作用正常至肿瘤性皮肤。此外，我们试图确定具体的转录本每个外泌体亚基在肿瘤发生过程中结合以促进肿瘤发生。具体目标：（1）确定外泌体亚基在疾病进展中的作用正常至肿瘤性皮肤；(2) 识别和表征相关转录本与外泌体亚基。研究设计：为了在更具临床相关性的环境中研究表皮稳态，我们生成 3 维完整的人类皮肤，包含人类表皮细胞（即在人类环境中，外泌体亚基已被永久敲除）真皮基质和基底膜在免疫受损的小鼠身上再生。通过使用该模型，我们可以对外泌体亚基进行功能丧失实验在再生人类皮肤中表征其在表皮生长、分化、并进展为肿瘤。我们将使用 CLIP-Seq 来确定相关的 RNA 在从正常表皮进展到肿瘤性表皮的过程中与外泌体亚基结合。