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Mechanosensitive remodeling of adherens junctions during snail-driven EMT

蜗牛驱动 EMT 过程中粘附连接的机械敏感重塑

基本信息

批准号：
10015324
负责人：
Mo Weng
金额：
$ 24.46万
依托单位：
UNIVERSITY OF NEVADA LAS VEGAS
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：
2018-09-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015324
关键词：
Address Adherens Junction Animals Apical Architecture Automobile Driving Behavior Biochemical Biochemical Pathway Caco-2 Cells Cell Line Cells Cellular biology Collaborations Development Disseminated Malignant Neoplasm Dominant-Negative Mutation Drosophila genus E-Cadherin Ectoderm Ectopic Expression Embryo Embryonic Development Epithelial Epithelial Cells Epithelium Event Fluorescence Resonance Energy Transfer Fluorescent Probes Genes Genetic Transcription Goals Human Image Individual Label Light Maintenance Malignant Neoplasms Measurement Measures Mechanics Medial Mediating Mentors Mesenchymal Mesoderm Mesoderm Cell Modeling Monitor Myosin ATPase Neoplasm Metastasis Phase Phenotype Play Positioning Attribute Postdoctoral Fellow Predisposition Primordium Process Proxy Psychological reinforcement RNA Interference Reagent Regulation Research Resolution Role Series Signal Transduction Snails System TNF gene Testing Time Tissues Work base density developmental disease epithelial stem cell epithelial to mesenchymal transition experimental study fluorescence lifetime imaging gastrulation genome-wide genome-wide analysis imaging biomarker in vivo in vivo Model mechanical force microscopic imaging mutant novel protein complex response sensor tissue/cell culture

项目摘要

Abstract/Project Summary Active remodeling of adherens junctions is crucial not only for keeping tissue integrity but also for driving the progression of many developmental events such as epithelial-mesenchymal-transition (EMT). Recent development in the research at the interface between cell biology and mechanical force has revealed that, in addition to the well studied biochemical signals, the mechanical tension plays an critical yet unappreciated role in the regulation of adherens junctions. The candidate's postdoc study has demonstrated that during Drosophila gastrulation adherens junctions in mesodermal primordium are repositioned and strengthened in response to apically localized myosin contraction. Such tension- dependent remodeling of adherens junctions protects junctions from Snail-driven junction disassembly and appear to developmentally time the EMT to occur only after the completion of the morphogenetic event. This establishes a model to study the mechanosensitive regulation of adherens junctions in an intact developmental system. The goal of the project is to elucidate the mechanism of tension-dependent adherens junction remodeling in the context of EMT. In the first aim, the dynamics of junctional components within individual junction clusters during the remodeling will be examined using photoconvertible fluorescent probes and in vivo junctional tension will be measured in live embryos using a FLIM (Fluorescence Lifetime Imaging Microscopy)-based FRET tension sensor that have been recently made and tested. In the second aim, a small yet comprehensive pool of direct Snail target genes identified from a recent genome-wide study will be tested for their roles in Snail-dependent junction disassembly. The identified genes will be further characterized in the independent phase. The last aim is to test the principle of tension-dependent junction remodeling and its impact on EMT in vertebrate cell lines in collaboration with McClatchey's lab. The cell lines with stably expressed live imaging markers will be made during the mentored phase. Junction dynamics and the role of mechanosensitive junction remodeling during EMT will be examined in the independent phase. Result from this project will advance our understanding on regulation of adherens junctions in response to myosin-generated tension and shed light on the novel function of Snail on disassembling junctions at post-transcriptional level during EMT.

抽象/项目总结