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Biomechanical mechanisms underlying the formation of the vertebrate body axis

脊椎动物体轴形成的生物力学机制

基本信息

批准号：
10738365
负责人：
Otger Campas
金额：
$ 27.37万
依托单位：
DRESDEN UNIVERSITY OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10738365
关键词：
3-Dimensional Actins Adult Affect Animals Behavior Biomechanics Biomedical Engineering Cell Shape Cell-Cell Adhesion Cells Chick Embryo Cultured Cells Data Development Disease Embryo Embryonic Structures Emulsions Gel Generations Glass Impairment In Situ Liquid substance Magnetism Malignant Neoplasms Maps Measures Mechanical Stress Mechanics Mesoderm Molds Molecular Morphogenesis Morphology Movement Myosin ATPase Myosin Type II N-Cadherin Nature Oils Organ Paraxial Mesoderm Physics Process Property Research Role Shapes Solid Stress Structure System Techniques Testing Tissue Engineering Tissues Variant Zebrafish biomechanical model cell motility clay diagnostic tool embryo tissue epithelial to mesenchymal transition experimental study in vivo insight malformation mechanical force monolayer non-muscle myosin novel prenatal regional difference response scoliosis simulation somitogenesis spatiotemporal tumor progression

项目摘要

PROJECT SUMMARY Sculpting tissues and organs into their 3D functional morphologies requires a tight spatiotemporal control of tissue mechanics. While cell-generated mechanical forces power morphogenesis, the resulting tissue flows that shape embryonic tissues in 3D depend strongly on the local tissue material properties, which govern the system's response to the internally generated forces. As a consequence, spatiotemporal variations in both mechanical forces and material properties can, independently or in combination, guide morphogenesis. The complexity of probing tissue mechanics within developing embryos has so far hindered our ability to dissect their specific roles and, more generally, to understand the biomechanical mechanisms that govern 3D tissue and organ morphogenesis. Using novel microdroplet-based techniques that the PI recently developed to measure both the tissue material properties and endogenous mechanical stresses within developing embryos, we propose to reveal the biomechanical mechanisms that underlie the formation of the zebrafish body axis. During posterior body axis elongation, cells display an anteroposterior gradient in their motility. Our preliminary data suggest that the anteroposterior variations in cellular movements may be caused by a transition between a fluid-like state of the tissue at the posterior end to a solid-like state in the presomitic mesoderm. Our hypothesis is that regional differences in fluid-like and solid-like tissue states control 3D tissue morphogenesis by enabling or restricting morphogenetic flows. Specifically, we hypothesize that during zebrafish body elongation the paraxial mesoderm transits from a fluid-like behavior in the tailbud to a solid-like behavior in the presomitic mesoderm, allowing tissue flows at the elongating body end while providing mechanical integrity to developmentally older structures, thereby guiding the nearly unidirectional tissue elongation of the body axis. In order to test this hypothesis, we plan to (1) measure and compare anteroposterior variations in tissue yield stress and endogenous mechanical stresses to establish the existence of fluid-like or solid-like tissue regions during body axis elongation, (2) establish how key functional molecules (actin, non-muscle myosin II and N-cadherin) control gradients in tissue mechanics and solid-like and fluid-like tissue states, and (3) integrate molecular, cell and tissue mechanics into a multiscale biomechanical model of body elongation. We believe this research will reveal a novel biomechanical mechanism of 3D tissue and organ morphogenesis, in which the spatial control of fluid-like and solid-like tissue regions guides the shaping of embryonic tissues. Moreover, it will dissect the specific roles of mechanical stresses and material properties in 3D tissue morphogenesis and establish how key functional molecules control tissue mechanics in vivo.

项目总结将组织和器官塑造成其3D功能形态需要严格的时空控制组织力学。当细胞产生的机械力为形态发生提供动力时，由此产生的组织流动在3D中塑造胚胎组织的能力很大程度上依赖于局部组织材料的特性，这些特性控制着系统对内部产生的力量的反应。因此，两者的时空变化机械力和材料特性可以独立地或组合地指导形态形成。这个到目前为止，在发育中的胚胎中探索组织力学的复杂性阻碍了我们解剖它们的具体作用，更广泛地说，是为了了解支配3D组织的生物力学机制器官形态发生。使用PI最近开发的基于微滴的新技术来测量组织材料特性和发育中胚胎的内源性机械应力，我们建议揭示斑马鱼体轴形成的生物力学机制。在身体后轴线上伸长时，细胞的运动性呈现前后梯度。我们的初步数据表明细胞运动的前后变化可能是由于细胞的流体状态之间的转变引起的在减数分裂前的中胚层中，后端的组织变为类固体状态。我们的假设是地区性类流体和类固体组织状态的差异通过启用或限制来控制3D组织形态发生形态发生流。具体地说，我们假设在斑马鱼身体伸长过程中，中胚层从尾芽中的类液体行为转变为分裂前中胚层中的类固体行为，允许组织在细长的身体末端流动，同时为发育中的老年人提供机械完整性结构，从而引导身体轴的近乎单向的组织伸长。为了测试这一点假设，我们计划(1)测量和比较组织屈服应力和组织屈服应力的前后变化内源性机械应力确定体内是否存在类液体或类固体组织区域轴延长，(2)确定关键功能分子(肌动蛋白、非肌肉肌球蛋白II和N-钙粘蛋白)如何控制组织力学和类固体和类流体组织状态的梯度，以及(3)将分子、细胞和组织力学转化为人体伸长的多尺度生物力学模型。我们相信这项研究将揭示3D组织和器官形态发生的一种新的生物力学机制，其中，类液体和类固体组织区域的空间控制指导着胚胎组织的形成。此外，它还将剖析机械应力和材料特性在3D组织中的具体作用形态发生和建立关键功能分子如何控制体内的组织力学。