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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.

摘要在神经系统发育期间，细胞和组织经常移动以组装成层和簇。要做到这一点，细胞需要产生力并将力传递给周围的环境来推动自己前进。体外研究已经确定了三个- 细胞如何在基板上移动的步进机构：细胞在迁移，粘附到衬底上并在背面分离。体内细胞是否使用同样的机制移动是不清楚的，因为实验的局限性阻碍了类似的研究。这个项目将解决这一挑战，并联合收割机一种新的蛋白质耗尽方法，提供高分辨率成像的时空控制来研究活体动物的组织是如何向前推进的。对于这些研究，我们将使用作为脊椎动物模型系统的斑马鱼后侧线原基迁移因为它对强大的遗传扰动和成像的顺从性。揭示迁移原基中力产生和传递的分子基础，将决定RhoA脉冲是如何产生的，RhoA诱导的细胞收缩是如何拉动细胞向前，是否局灶性粘连通过细胞传递产生的力收缩到周围环境以及周围环境如何响应摩擦力。由于RhoA信号传导和粘着斑组分在人类中是保守的，拟议的研究将提供必要的背景，以更好地建模和理解发育神经系统缺陷，并告知策略，以纠正这些缺陷。