CAREER: Physical Shaping of Multicellular Mesenchymal Tissues

在发育早期，间充质细胞迁移、重排和改变形状以重塑胚胎。在早期胚胎中，松散排列的间充质细胞的协调运动构成了脊椎动物的身体平面并填充组织，为肌肉、结缔组织和骨骼以及淋巴和循环系统的构建做准备。许多基因和许多细胞参与了这些活动，但几乎没有实验证据表明，基因和细胞如何产生物理力，并整合生化途径来驱动胚胎内的机械运动。本研究的目的是研究基因如何通过以下方式控制多细胞间充质组织的物理机制：1)分析重新聚集的物理学和负责组织塑造快速阶段的细胞学；2)在不同的微环境中挑战细胞并评估它们的行为变化；3)不同水平的细胞黏附分子和表面收缩能力，以揭示间充质组织的扩散和吞噬是如何机械协调的。理解调控间充质组织有序组装规则的分子基础将解释亚细胞水平的事件如何在器官和功能组织组装过程中协调细胞行为。这些发现将补充和扩展理解间充质形态发生的分子基础的努力，并开始将分子机制整合到更大的“形态发生”过程中，这些过程是健壮的，可能会被组织工程师适应。该项目产生的跨学科和跨学科培训将为生物学家和组织工程师提供将所学概念整合到一个框架中的能力，这对这两个领域都将是重要的。

During early development mesenchymal cells migrate, rearrange, and change shape to remodel the embryo. Coordinated movements of loosely-packed mesenchymal cells in the early embryo construct the vertebrate body plan and populate tissues in preparation for the construction of muscles, connective tissue and bone, as well as the lymphatic and circulatory systems. Many genes and many cells participate in these events, but there is little experimental evidence on how genes and cells generate physical forces and integrate biochemical pathways to drive mechanical movements within embryos. The goal of this research is to investigate how genes control the physical mechanics of multicellular mesenchymal tissues by: 1) analyzing the physics of re-aggregation and the cellular mechanics responsible for rapid phases of tissue sculpting, 2) challenging cells with varied micro-environments and assessing how their behavior changes, and 3)vary levels of cell adhesion molecules and surface contractility to reveal how mesenchymal tissue spreading and engulfment are mechanically coordinated. Understanding the molecular basis of rules governing the ordered assembly of mesenchymal tissue will explain how events at the subcellular scale coordinate cell behaviors during assembly of organs and functional tissues. These findings will complement and extend efforts to understand the molecular basis of mesenchymal morphogenesis and begin the process of integrating the molecular machinery into larger "morphogenetic" processes that are robust and may be adapted by tissue engineers. The cross- and interdisciplinary training resulting from this project will provide biologists and tissue engineers the ability to integrate learned concepts into a framework the will be important for both fields.