Deciphering mechanisms that drive collective cell migration

破译驱动集体细胞迁移的机制

基本信息

批准号：
10917532
负责人：
Pamela K Kreeger
金额：
$ 32.87万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10917532
关键词：
3-Dimensional Actins Biochemical Biocompatible Materials Biological Assay Biophysical Process Biophysics Breast Cancer Cell Cell model Cell physiology Cells Cellular Structures Chemicals Chronic Collaborations Coupling Cues Cytoskeleton Decision Making EGF gene Elements Environment Epidermal Growth Factor Receptor Epithelium Event Fluorescence Resonance Energy Transfer Foundations Genetic Goals Growth Factor Health Human Human Development Impairment Individual Intercellular Junctions Intervention Knowledge Link Malignant Neoplasms Methods Molecular Monitor Motion Movement PLC gamma1 Pathologic Pathology Pathway interactions Pattern Process Reporter Signal Transduction Stimulus Tissues Traction Force Microscopy Translating Travel Work biophysical tools cell behavior cell motility experimental study healing human tissue innovation insight keratinocyte migration novel optogenetics repaired spatiotemporal tissue repair tool transmission process

项目摘要

PROJECT SUMMARY Collective cell migration is the most prevalent form of cell migration in the body; it is involved in the construction and repair of almost all human tissues. Previous work by the PIs has provided novel insight on the hierarchy of individual cell behaviors and intracellular signals that drive collective migration. This work identified activation of the intracellular signal PLCg1 as strongly correlated with increased collective migration and cell migration persistence. The proposed study aims to elucidate the mechanisms by which PLCg1 drives collective migration and will yield both novel tools and knowledge that may be applied to control this process. We will achieve this goal by: 1) Determining the mechanism(s) by which PLCg1 activation yields cytoskeletal remodeling. We will develop a FRET-based PLCg1 reporter and identify the downstream effectors of PLCg1 that drive cytoskeletal rearrangement, a critical component of cell movement. 2) Elucidating the biophysical mechanisms by which PLCg1 activation translates into directed collective migration. We will develop cellular models with varying levels of constitutively active PLCg1 and apply traction force microscopy to analyze how cytoskeletal forces are transmitted to yield collective cell movement. 3) Determining optimal patterns and extent of PLCg1 activation needed for robust collective migration. We will develop an optogenetic approach to stimulate different spatio-temporal dynamics of PLCg1 activation during directed keratinocyte migration. By employing a combination of innovative molecular and biophysical tools, we aim to uncover mechanistic knowledge that allows us to gain control over collective epithelial migration. Identifying the pathway(s) by which PLCg1 activation connects to downstream signals, as well as its spatial and temporal dynamics within the collective sheet, provides opportunities to regulate both healthy and pathological collective migration across a range of tissues and pathologies. Elucidation of these pathways and cues provides an important foundation for targeting specific elements to induce collective movement in conditions where it is impaired (e.g., chronic would healing) or to halt collective movement in conditions where it is pathological (e.g., cancer).

项目摘要集体细胞迁移是体内最普遍的细胞迁移形式。它参与了建筑并修复几乎所有人类组织。 PI的先前工作提供了有关层次结构的新颖见解驱动集体迁移的单个细胞行为和细胞内信号。这项工作确定了激活细胞内信号PLCG1与集体迁移和细胞迁移密切相关持久性。拟议的研究旨在阐明PLCG1驱动集体迁移的机制并将产生可用于控制这一过程的新颖工具和知识。我们将实现这一目标目标作者： 1）确定PLCG1激活产生细胞骨架重塑的机制。我们将发展基于FRET的PLCG1记者，并识别驱动细胞骨架的PLCG1的下游效应子重排，细胞运动的关键组成部分。 2）阐明PLCG1激活转化为定向集体的生物物理机制迁移。我们将开发具有不同组成型活性PLCG1的细胞模型，并应用牵引力显微镜分析如何传播细胞骨架力以产生集体细胞移动。 3）确定可靠的集体迁移所需的最佳模式和PLCG1激活的程度。我们将开发一种光遗传学方法来刺激PLCG1激活的不同时空动力学在定向角质形成细胞迁移期间。通过结合创新的分子和生物物理工具，我们旨在发现机械使我们能够控制集体上皮迁移的知识。识别途径 PLCG1激活连接到下游信号及其空间和时间动态集体表，提供了调节健康和病理集体迁移的机会组织和病理范围。阐明这些途径和提示为针对特定元素在受损的条件下诱导集体运动（例如，慢性愈合）或在病理性的条件下（例如癌症）中停止集体运动。