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

• 批准号: 10152375
• 负责人: Otger Campas
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152375
• 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; Diagnostic; Disease; Embryo; Embryonic Structures; Emulsions; Gel; Generations; Glass; Impairment; In Situ; Liquid substance; Magnetism; Malignant Neoplasms; Maps; Measures; Mechanical Stress; Mechanics; Mesoderm; Mesoderm Cell; 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; base; biomechanical model; cell motility; clay; embryo cell; embryo tissue; epithelial to mesenchymal transition; experimental study; in vivo; insight; malformation; mechanical force; non-muscle myosin; novel; prenatal; regional difference; response; scoliosis; simulation; somitogenesis; spatiotemporal; tool; tumor

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. !

项目概要 将组织和器官雕刻成 3D 功能形态需要严格的时空控制 组织力学。虽然细胞产生的机械力为形态发生提供动力，但产生的组织流动 在 3D 中塑造胚胎组织在很大程度上取决于局部组织材料特性，这些特性控制着 系统对内部产生的力的反应。因此，两者的时空变化 机械力和材料特性可以独立或组合地指导形态发生。这 迄今为止，探测发育中胚胎内组织力学的复杂性阻碍了我们解剖的能力 它们的具体作用，更广泛地说，是了解控制 3D 组织的生物力学机制 和器官形态发生。 使用 PI 最近开发的基于微滴的新型技术来测量组织材料 发育胚胎中的特性和内源性机械应力，我们建议揭示 斑马鱼身体轴形成的生物力学机制。在身体后轴期间 随着伸长，细胞的运动表现出前后梯度。我们的初步数据表明 细胞运动的前后变化可能是由流体状态之间的转变引起的 前体中胚层后端的组织转变为固体状态。我们的假设是区域 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。具体来说，我们假设在斑马鱼身体伸长过程中，近轴 中胚层从尾芽中的流体状行为转变为前体中胚层中的固体状行为， 允许组织在伸长的身体末端流动，同时为发育中的老年人提供机械完整性 结构，从而引导身体轴几乎单向的组织伸长。为了测试这个 假设，我们计划（1）测量和比较组织屈服应力的前后变化 内源性机械应力以确定体内流体状或固体状组织区域的存在 轴伸长，(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）的作用 控制组织力学以及类固体和类流体组织状态的梯度，以及（3）整合分子、细胞 和组织力学转化为身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新生物力学机制， 其中类流体和类固体组织区域的空间控制指导胚胎组织的成形。 此外，它将剖析机械应力和材料特性在 3D 组织中的具体作用 形态发生并确定关键功能分子如何控制体内组织力学。 ！