Micromechanical Determinants of Organ Design and Engineering (SysCODE 6 of 10)

这项提案的主要目标(U54联盟赠款的项目6，共11个，标题为“SysCODE：基于系统的 器官设计和工程联合会“)是为了定义工程原理和微观结构 设计标准，当与该联盟发现的分子蓝图相结合时，将允许我们 制造具有适当机械和化学信号的仿生材料，以诱导 器官再生。我们将定义由组织细胞产生的微机械力是如何被 具有不同机械柔度和内部微结构的细胞外基质(ECM)有助于 局部到局部的组织形态改变和渐进性结构重塑 复杂器官的形态发生和分级自组装。长期目标是利用体能 在制造可重新编程的多功能仿生支架的努力中确定了设计标准 干细胞来重塑器官的形成。这些支架将模仿生物的微观机械特征 控制细胞命运局部切换的ECM，并将在空间上定向化学物质和粘合剂信号。 引发适当的发展级联反应。为了确定基本的设计原则，我们将细分 该分层自组装过程被分成单独的步骤或关键的“形态发生模块”，(例如， 间充质凝聚、上皮萌发和折叠、细胞命运转换和上皮-间充质 过渡)，是牙齿发育过程中上皮-间充质相互作用的基础，以及 胰岛和心脏瓣膜。相关分子调节剂与高通量ECM制备 战略将通过与该联盟其他成员的合作获得。新的 然后，本建议书中发现的信息、ECM材料和设计标准将与 为组织和器官工程开发原型材料的其他项目。具体目标包括：1) 分析细胞产生的收缩力和ECM微观力学在空间上的变化 牙齿发育过程中的形态发生变化，2)确定改变的效果 内源性细胞产生的拉力或对牙齿发育施加外部机械载荷， 3)确定改变人工ECM的力学、结构和化学成分对其的影响 牙齿、胰岛和心脏瓣膜的形态发生和细胞命运转换。

The main goal of this proposal (Project 6 of 11 of a U54 Consortium grant entitled, "SysCODE: Systemsbased Consortium for Organ Design and Engineering") is to define engineering principles and microstructural design criteria that when combined with the molecular blueprint uncovered by this Consortium will permit us to fabricate biomimetic materials with appropriate mechanical and chemical signals necessary to induce organ regeneration. We will define how micromechanical forces generated by tissue cells and resisted by extracellular matrices (ECMs) with different mechanical compliance and internal microstructure contribute locally to the regional tissue shape transformations and progressive structural remodeling that mediate morphogenesis and hierarchical self assembly of complex organs. The long term goal is to use the physical design criteria identified in this effort to fabricate multifunctional biomimetic scaffolds that can reprogram stem cells to recapitulate organ formation. These scaffolds will mimic the micromechanical features of living ECMs that control cell fate switching locally, and will spatially orient chemical and adhesive signals that. trigger appropriate developmental cascades. To identify fundamental design principles, we will break down this hierarchical self assembly process into individual steps or critical "morphogenetic modules" ,(e.g., mesenchyme condensation, epithelial budding and folding, cell fate switching, and epithelial-mesenchymal transitions) that underlie epithelial-mesenchymal interactions during development of the tooth, as well as pancreatic islets and heart valves. Relevant molecular regulators and high throughput ECM fabrication strategies will be accessed through collaboration with other members of this Consortium. The new information, ECM materials and design criteria discovered in this proposal will then be integrated with the other projects to develop prototype materials for tissue and organ engineering. The specific aims include: 1) To analyze how cell-generated contractile forces and ECM micromechanics vary spatially during morphogenetic shape transformations in the developing tooth, 2) To determine the effects of altering endogenous cell-generated tensional forces or applying external mechanical loads on tooth development, and 3) To determine the effects of varying the mechanics, structure and chemistry of artificial ECMs on morphogenesis and cell fate switching in tooth, pancreatic islet and heart valve.