Biomechanics of tissue motility

组织运动的生物力学

基本信息

批准号：
10430282
负责人：
Holger Knaut
金额：
$ 54.57万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10430282
关键词：
Actins Address Animals Back Basement membrane Biological Models Biomechanics Cell Shape Cells Computer-Assisted Image Analysis Cultured Cells Cytoskeleton Defect Development Disease Embryo F-Actin Feedback Fibroblast Growth Factor Focal Adhesions Friction Future Generations Genetic Homeostasis Human Human Development Image Impairment In Vitro Integrins Mediating Medical Modeling Molecular Motor Movement Muscle Myosin Type II Nervous system structure Optics Pattern Periodicity Physiologic pulse Primordium Process Protein Kinase Proteins Role Shapes Signal Pathway Signal Transduction Skin System Talin Testing Tissues Traction Zebrafish cell motility chemokine conditional mutant experimental study high resolution imaging human disease in vivo lateral line migration mutant nerve stem cell nervous system development nervous system disorder novel pathogen public health relevance response rho transmission process wound healing

项目摘要

ABSTRACT During nervous system development, cells and tissues often move to assemble into layers and clusters. To do this, the cells need to generate force and transmit force to their surroundings to push themselves forward. In vitro studies have identified a three- step mechanism for how cells move on a substrate: cells protrude in the direction of migration, adhere to the substrate and detach in the back. Whether cells in vivo use the same mechanism to move is unclear because experimental limitations have hindered similar studies. This project will address this challenge and combine a novel protein depletion approach that offers spatial and temporal control with high resolution imaging to ask how a tissue pushes itself forward in a living animal. For these studies, we will use the zebrafish posterior lateral line primordium migration as a vertebrate model system because of its amenability to powerful genetic perturbations and imaging. To reveal the molecular basis of force generation and transmission in the migrating primordium, we will determine how RhoA pulses are generated, how RhoA-induced cell contractions pull cells forward, whether focal adhesions transmit the force generated through cell contractions to the surroundings and how the surroundings respond to the friction force. Since RhoA signaling and focal adhesion components are conserved in humans, the proposed studies will provide necessary context to better model and understand developmental nervous system defects and inform strategies to correct these defects.

抽象的在神经系统发育过程中，细胞和组织经常移动组装成层和簇。为此，细胞需要产生力并将力传递给周围的环境推动自己前进。体外研究已经确定了三细胞如何在基质上移动的步进机制：细胞朝以下方向突出迁移，粘附到基材上并在背面分离。体内细胞是否利用由于实验限制阻碍了相同的移动机制尚不清楚类似的研究。该项目将解决这一挑战并结合一种新型蛋白质通过高分辨率成像提供空间和时间控制的耗尽方法询问活体动物的组织如何推动自身前进。对于这些研究，我们将使用斑马鱼后侧线原基迁移作为脊椎动物模型系统因为它能够承受强大的遗传扰动和成像。为了揭示迁移原基中力产生和传递的分子基础，我们将决定 RhoA 脉冲如何产生、RhoA 诱导的细胞收缩如何拉动细胞向前移动，粘着斑是否传递通过细胞产生的力对周围环境的收缩以及周围环境对摩擦力的反应。由于 RhoA 信号传导和粘着斑成分在人类中是保守的，拟议的研究将为更好地建模和理解提供必要的背景发育神经系统缺陷并提供纠正这些缺陷的策略。