Morphogenetic Tissue Movements in Early Embryos

早期胚胎的形态发生组织运动

• 批准号: 9119848
• 负责人: ANDRAS CZIROK
• 金额: $ 28.64万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119848
• 关键词: Animal Model; Applications Grants; Behavior; Biological Assay; Biomechanics; Birds; Blood; Cartilage; Cells; Complex; Computer Simulation; Congenital Abnormality; Contracts; Cues; Data; Development; Discipline; Embryo; Endoderm Cell; Environment; Event; Exhibits; Extracellular Matrix; Future; Gel; Germ Layers; Goals; Growth; Health; Human; Image; Image Analysis; Individual; Knowledge; Laws; Life; Link; Measurement; Mechanical Stress; Mechanics; Methods; Modeling; Molds; Morphogenesis; Morphology; Movement; Normal tissue morphology; Optics; Organ; Outcome; Pathologic Processes; Physiological Processes; Positioning Attribute; Primitive foregut structure; Process; Property; Relaxation; Research; Rheology; Stress; Structure; Tissue Engineering; Tissues; Traction; Wound Healing; base; blastomere structure; bone; cancer cell; cell motility; computerized tools; insight; mathematical model; microscopic imaging; millimeter; molecular imaging

DESCRIPTION (provided by applicant): Tissue engineering, the controlled construction of tissues - cells and their extracellular matrix (ECM) environment - is a promising avenue of future biomedical applications. To realize this possibility, the dynamic and mutually interdependent relationship between cells and ECM has to be understood. The long-term goal of our research is to understand the interplay between cell and tissue dynamics during embryonic morphogenesis. In particular, the early avian embryo is an anatomically and experimentally tractable warm-blooded model organism, exhibiting a morphogenic sequence comparable in complexity to that of human embryos. The objective of this grant application is to provide a comprehensive and predictive computational model of the caudal avian embryo during the first day of development. The model will explain how tissue movements arise from the collective action of its constituent cells. Our central hypothesis is that the body plan of early amniote embryos is not established by "conventional" cell motility -- i.e., cells migrating on a rigid substrate to pre-defined positins following environmental cues. Instead, germ layers and the entire embryo morphology are molded to a large extent by cell- exerted mechanical forces (stresses) and their controlled dissipation/relaxation as well as cells moving by gaining traction from adjacent cells, cellular activities dubbed as "nonconventional motility" in this application. We propose a synergistic approach combining advanced imaging, molecular and mechanical perturbations, micro-rheology measurements, and computational modeling. Specifically, we propose to i) determine the contributions of "conventional" vs. "non-conventional" cell motility in the morphogenetic processes of early avian embryos, ii) identify the mechanical basis of "non- conventional" cell motility in early avian embryos, and iii) develop computational models to derive tissue-level growth laws from cellular activities. The empirical data generated during the proposed research will fill a gap in our knowledge of how most embryonic cells and the surrounding ECM moves during early development, and what are the corresponding spatio-temporal dynamics of mechanical stress within the tissues. The data will clarify the mechanism of a prevalent yet understudied mode of collective cell motility. Our efforts will create the first model that explain complex movements of a millimeter-sized piece of living material by resolving and relating events both at the tissue and individual cell level. Advanced optical microscopy and image analysis methods, as well as the resulting computational tools will enable future studies of more differentiated and functional tissues and increase our understanding of the tissue mechanics underlying physiological and pathological processes: such as bone and cartilage remodeling, wound healing or malignant cell invasion.

描述（由申请人提供）：组织工程，组织-细胞及其细胞外基质（ECM）环境的受控构建-是未来生物医学应用的一条有前途的途径。为了实现这种可能性，必须理解细胞和ECM之间的动态和相互依赖的关系。我们研究的长期目标是了解胚胎形态发生过程中细胞和组织动力学之间的相互作用。特别是，早期鸟类胚胎是一种解剖学和实验上易于处理的温血模式生物，表现出与人类胚胎相似的复杂性形态发生序列。这项资助申请的目的是提供一个全面的和预测性的计算模型的尾禽胚胎在第一天的发展。该模型将解释组织运动是如何从其组成细胞的集体行动中产生的。我们的中心假设是，早期胚胎的身体计划不是由“传统”细胞运动建立的，即，细胞在刚性基质上迁移到预定位置，以遵循环境线索。相反，胚层和整个胚胎形态在很大程度上是由细胞施加的机械力（应力）及其受控的消散/松弛以及通过从相邻细胞获得牵引力而移动的细胞（在本申请中称为“非常规运动性”的细胞活动）塑造的。我们提出了一种协同的方法，结合先进的成像，分子和机械扰动，微流变学测量和计算建模。具体而言，我们建议i）确定早期禽类胚胎的形态发生过程中“常规”与“非常规”细胞运动性的贡献，ii）确定早期禽类胚胎中“非常规”细胞运动性的机械基础，以及iii）开发计算模型以从细胞活动导出组织水平的生长规律。在拟议的研究过程中产生的经验数据将填补我们对大多数胚胎细胞和周围ECM在早期发育过程中如何移动以及组织内机械应力的相应时空动态的知识空白。这些数据将阐明一种普遍但研究不足的集体细胞运动模式的机制。我们的努力将创建第一个模型，通过在组织和单个细胞水平上解决和关联事件来解释毫米大小的生命物质的复杂运动。先进的光学显微镜和图像分析方法，以及由此产生的计算工具，将使更多的分化和功能组织的未来研究，并增加我们对组织力学的生理和病理过程的理解：如骨和软骨重塑，伤口愈合或恶性细胞入侵。