CAREER: Physical Shaping of Multicellular Mesenchymal Tissues

在早期发育过程中，间充质细胞迁移，重新排列和改变形状以重塑胚胎。在早期胚胎中，松散包装的间充质细胞的协调运动构建了脊椎动物的身体结构，并为肌肉、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事件，但几乎没有实验证据表明基因和细胞如何产生物理力量并整合生化途径来驱动胚胎内的机械运动。本研究的目标是通过以下方式研究基因如何控制多细胞间充质组织的物理力学：1）分析重新聚集的物理学和负责组织塑造的快速阶段的细胞力学，2）用不同的微环境挑战细胞并评估它们的行为如何变化，和3）改变细胞粘附分子和表面收缩性的水平，以揭示间充质组织的伸展和吞噬是如何机械协调的。了解间充质组织有序组装规则的分子基础将解释在器官和功能组织组装过程中，亚细胞尺度的事件如何协调细胞行为。这些发现将补充和扩展努力，以了解间充质形态发生的分子基础，并开始的过程中整合的分子机制到更大的“形态发生”的过程是强大的，并可能适应组织工程师。该项目产生的交叉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，这对两个领域都很重要。

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.