Core1: Computational

核心1：计算

基本信息

批准号：
10688253
负责人：
Vivek Shenoy
金额：
$ 34.14万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688253
关键词：
3-Dimensional Actomyosin Adhesions Adhesives Affect Basement membrane Blood Platelets Blood Vessels Cell Adhesion Cell Adhesion Molecules Cell Death Cell Nucleus Cell Survival Cell model Cells Characteristics Chromatin Chromatin Structure Coupling Cytoskeleton DNA Damage Data Analytics Dimensions Elements Endothelial Cells Endothelium Environment Epigenetic Process Extracellular Matrix Extravasation Feedback Fractals Gene Expression Gene Expression Regulation Genetic Transcription Genome Grain Growth Histone Deacetylation Image In Vitro Individual Invaded Lamin Type A Lamins Length Liquid substance Liver Mechanical Stress Mechanics Mediating Modeling Modification Molecular Morphology Myosin Type II Neoplasm Metastasis Nuclear Nuclear Envelope Nuclear Lamina Organ Pattern Peptide Hydrolases Phenotype Process Property Regulation Role Rupture Shapes Skin Solid Stress Structure Theoretical model Time Tissues Tumor Cell Migration biophysical model cancer cell cell motility computerized tools coping experimental study extracellular in vivo innovation insight mechanotransduction migration multi-scale modeling neoplastic cell nucleocytoplasmic transport response shear stress simulation stressor three-dimensional modeling tool transcriptome

项目摘要

Computational Core (Core A): SUMMARY To guide and interpret the in vitro (Project 1) and in vivo experiments (Project 2) and to provide a physical basis for changes in transcriptional patterns in response to mechanical stresses (Core B), this core will employ an array of computational tools spanning a wide range of length and time scales. These include models for cell adhesion, cytoskeletal function, cell-matrix interactions and 3D multiscale models for nuclear mechano- transduction and chromatin organization. This suite of modeling tools will reveal non-linear interactions between cell and nuclear deformation during of extravasation and migration, mechano-adaptation in response to fluid and solid stresses, intravascular and extravascular niche properties and cell death for individual compared to clustered CTCs. Significantly, modelling of 3D genome organization will allow us to elucidate the relationship between the mechanics of the cell, chromatin organization, and transcription, thus providing new insights on how mechanical stresses regulate gene expression during metastasis, and identification of reversible and persisting chromatin deformation associates with cell survival or death. Cancer cells invade individually or collectively, but the factors that govern their strategies to colonize the tissue and their ability to survive intravascular stress and extravasation are poorly understood. While the coupling between cell contractility, nuclear mechanotransduction, and adhesive interactions with the ECM and vessel wall is known to affect cell adhesion and motility, the effects of this interplay on cell survival has yet to be rigorously investigated. To elucidate the physical mechanisms involved in such regulation, we developed 3D chemo- mechanical models to describe the three-way feedback between the adhesions, the cytoskeleton, and the nucleus. The model shows local tensile stresses generated at the interface of the cell and the extracellular environment regulate the properties of the nucleus, including nuclear morphology, levels of lamin A/C, histone deacetylation and nucleo-cytoplasmic shuttling of YAP/TAZ, which in turn govern spatial chromatin organization, gene expression and the ability of the cells to survive and cope with the mechanical stresses. Building on these tools, the specific aims of this project are: · Aim 1. Predict the role of vascular flow on tumor cell arrest and survival in the intravascular niche. · Aim 2. Model the mechanochemical/molecular mechanisms of individual/collective extravasation of CTCs. · Aim 3. Predict the influence of alterations in chromatin organization and transcriptional patterns induced by intravascular stress and extravasation on the survival and growth of migrating tumor cells

计算核心（核心A）：摘要指导和解释体外（项目1）和体内实验（项目2）并提供物理基础对于响应机械应力的转录模式的变化（核心B），该核心将员工一系列计算工具，涵盖了一系列长度和时间尺度。这些包括细胞的模型粘附，细胞骨架功能，细胞 - 矩阵相互作用和核机械的3D多尺度模型转导和染色质组织。这套建模工具将揭示非线性相互作用渗出和迁移期间的细胞和核变形，响应液体和机械适应与个人相比聚集的CTC。值得注意的是，3D基因组组织的建模将使我们能够阐明关系在细胞的力学，染色质组织和转录之间，从而提供了有关如何机械应力可调节转移过程中基因表达，并鉴定可逆和持续染色质变形与细胞存活或死亡相关。癌细胞单独或集体入侵，但是控制组织策略的因素他们的生存能力在血管内压力和渗出的能力上鲜为人知。耦合在细胞收缩力，核机械转导和与ECM和容器壁的粘合剂相互作用之间已知会影响细胞粘合剂和运动性，该相互作用对细胞存活的影响尚未严格调查。为了阐明这种调节所涉及的物理机制，我们开发了3D化学机械模型描述粘连，细胞骨架和粘附之间的三向反馈核。该模型显示在细胞的界面和细胞外产生的局部拉伸应力环境调节核us的性质，包括核形态，层粘连蛋白A/C的水平，组蛋白 YAP/TAZ的脱乙酰化和核胞质穿梭，这又控制了空间染色质组织，基因表达以及细胞生存和应对机械应力的能力。建立在这些基础上工具，该项目的具体目的是： ·目标1。预测血管流动对肿瘤细胞停滞和血管内生物中的生存的作用。目标2。建模个体/集体渗出的机械化学/分子机制 CTC。目标3。预测染色质组织和转录模式中改变的影响由血管内应激和对迁移肿瘤生存和生长的渗出引起的诱导细胞