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Nuclear mechanobiology in confined migration

受限迁移中的核力学生物学

基本信息

批准号：
10724706
负责人：
Jan Lammerding
金额：
$ 8.7万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724706
关键词：
3-Dimensional Attention Biological Assay Cell Cycle Progression Cell Line Cell Nucleus Cell Survival Cell physiology Cells Cellular Structures Characteristics Chromatin Circulation Clinical Collagen Complement Custom Cytoplasm DNA DNA Damage DNA replication fork Data Development Distant Environment Event Exhibits Extracellular Matrix Face Fibroblasts Gene Expression Genetic Transcription Genome Stability Genomic DNA Genomics Goals Homeostasis Image Immune Immune response Immunofluorescence Immunologic Invaded Label Lead Mechanical Stress Mechanics Microfluidic Microchips Mitochondria Modeling Molecular Molecular Biology Molecular Conformation Molecular Genetics Neoplasm Metastasis Normal Cell Nuclear Nuclear Envelope Organelles Pathway interactions Physically Challenged Physiological Physiological Processes Play Production Reactive Oxygen Species Reporter Reporting Research Role Rupture Site Stress System Therapeutic Time Tissues Variant Visualization cancer cell cell fixing cell motility cell type chromatin modification experimental study falls genome-wide genome-wide analysis improved in vivo inflammatory modulation insight interstitial live cell imaging migration neoplastic cell novel nuclease programs replication stress response senescence targeted treatment temporal measurement therapy resistant treatment response tumor progression tumorigenic wound healing

项目摘要

Project Summary Cell migration is essential for numerous physiological processes, including development, tissue homeostasis, and wound healing. At the same time, cell migration enables tumor cells to invade other tissues, enter/exit the circulation, and spread to distant sites in the body to form metastases. While these facts have motivated research on cell migration for many decades, one aspect that has only recently received attention is the physical challenge that cells face during migration in three-dimensional (3D) environments, and the resulting impact on cellular structure and function. In tissues, cells frequently move through tight spaces that require substantial deformation of the cell nucleus, which is the largest and stiffest organelle. The associated mechanical stress can result in nuclear envelope rupture, DNA damage, and changes in genomic organization. Many questions, however, remain, including the underlying molecular mechanisms, the functional consequences, and the variability across different cell lines. The central goal of this proposal is to identify the characteristic changes in chromatin organization associated with confined migration, determine the molecular mechanisms responsible for the mechanically-induced changes in chromatin organization and DNA damage, and assess the functional consequences of these events. To achieve this goal, we have developed novel experimental platforms that enable extended live-cell imaging of cells migrating through precisely-defined microenvironments while visualizing nuclear deformation, nuclear envelope rupture, DNA damage, and chromatin modifications. These platforms will be paired with molecular biology approaches and assays for genome-wide analysis of changes in 3D chromatin organization and gene expression in a panel of well-characterized cell lines representing both tumorigenic and non-tumorigenic cells. In the first aim, we will identify migration-induced changes in chromatin organization and gene expression, determine the molecular mechanisms responsible for altered chromatin organization, and assess the functional consequences of the altered chromatin organization. In the second aim, we will identify the molecular mechanisms for DNA damage during confined migration and determine the impact of migration-induced DNA damage on cell viability, cell cycle progression, and senescence. We will focus our studies on the earliest events resulting from altered chromatin organization and DNA damage, which we expect to exhibit less variation across multiple cell types than longer-term effects. Our ultimate goal is to uncover general principles in nuclear mechanobiology that will lead to an improved understanding of the impact of migration through tight spaces on cellular function and genomic stability, including the activation or suppression of specific transcriptional programs that may further enhance cell migration or modulate other cellular functions. Insights gained from these studies may help guide therapeutic approach for a variety of clinical conditions, from wound healing and immune-responses to therapies targeting metastatic tumor cells.

项目总结