Morphogenetic Tissue Movements in Early Embryos

早期胚胎中的形态发生组织运动

• 批准号: 8921214
• 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/8921214
• 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; Microscopy; 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; 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，即组织（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个有前途的途径。为了实现这种可能性，必须了解细胞和 ECM 之间动态且相互依赖的关系。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型生物，其形态发生序列的复杂性与人类胚胎的复杂性相当。该拨款申请的目的是提供尾部鸟类胚胎发育第一天的全面和预测计算模型。该模型将解释组织运动如何由其组成细胞的集体行动产生。我们的中心假设是，早期羊膜动物胚胎的身体计划不是通过“传统”细胞运动建立的——即细胞根据环境线索在刚性基质上迁移到预先定义的位置。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）及其受控的耗散/松弛以及细胞通过获得相邻细胞的牵引力而移动而塑造的，在本申请中细胞活动被称为“非常规运动”。我们提出了一种结合先进成像、分子和机械扰动、微流变测量和计算建模的协同方法。具体来说，我们建议i）确定“常规”与“非常规”细胞运动在早期禽类胚胎形态发生过程中的贡献，ii）确定早期禽类胚胎中“非常规”细胞运动的机械基础，以及iii）开发计算模型以从细胞活动中推导出组织水平的生长规律。在拟议的研究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相应的时空动力学的了解的空白。这些数据将阐明一种普遍但尚未得到充分研究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，通过在组织和个体细胞水平上解决和关联事件来解释毫米大小的生物材料的复杂运动。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未来能够研究更多分化和功能性组织，并增加我们对生理和病理过程背后的组织力学的理解：例如骨和软骨重塑、伤口愈合或恶性细胞侵袭。