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Post-Transcriptional Regulators of Epidermal Homeostasis and Neoplasia

表皮稳态和肿瘤的转录后调节因子

基本信息

批准号：
9916713
负责人：
GEORGE L SEN
金额：
$ 38.15万
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：
2018-07-18 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916713
关键词：
3&apos Untranslated Regions 3-Dimensional Address Atrophic Basal cell carcinoma Basement membrane Binding Cells Complex Dermal Development Differentiation and Growth Disease Epidermis Epithelial Epithelium Equilibrium Event Foundations Generations Genetic Transcription Genetic Translation Growth Homeostasis Human Immune Lead Malignant Neoplasms Mediating Messenger RNA Modeling Molecular Mus Natural regeneration Neoplasms Organism Pathway interactions Play Population Post-Transcriptional Regulation Process Proteins Psoriasis Publications Publishing RNA RNA Helicase Regulation Research Design Role Skin Squamous cell carcinoma Structure Transcript Translating Translations Tumor stage Water Work cancer site chronic wound clinically relevant crosslinking and immunoprecipitation sequencing design epidermal stem cell experimental study in vivo insight knock-down loss of function mRNA Transcript Degradation member messenger ribonucleoprotein neoplastic novel strategies overexpression premature prevent protein degradation prototype self-renewal skin disorder stem cells therapy development tumor tumor initiation tumor progression tumorigenesis

项目摘要

Project Summary/Abstract Background: Transcriptional mechanisms that regulate epidermal homeostasis 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 RNA helicase DDX6 is necessary to maintain epidermal self-renewal through the mRNA degradation and translation pathway. By associating with specific members of the translation pathway DDX6 binds to and mediates the translation of self- renewal and proliferation transcripts to maintain self-renewal. DDX6 also associates with mRNA degradation proteins to bind differentiation-inducing transcripts to promote their degradation to prevent premature differentiation. Objective/hypothesis: This proposal seeks to understand the regulation of epidermal homeostasis and tumor initiation through post-transcriptional mechanisms. We previously identified proteins associated with DDX6 and our objective is to characterize the role of each protein in regulating epidermal growth, differentiation, and progression to neoplasia as well as the mechanisms of action. Furthermore we seek to determine the specific transcripts that DDX6 and its associated complexes bind during homeostasis and tumor initiation. Specific Aims: (1) To determine the role of DDX6 associated proteins on epidermal homeostasis and tumor initiation and (2) to identify and characterize the transcripts associated with DDX6 complexes. 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 either DDX6 or its associated proteins) 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 DDX6 and its associated proteins in regenerated human skin to characterize their role in epidermal growth, differentiation, and progression to neoplasia. We will also use CLIP- Seq to determine the RNAs associated with DDX6 complexes during the progression from normal to neoplastic epidermis.

项目总结/文摘