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

器官设计与工程的微机械决定因素（SysCODE 6 of 10）

• 批准号: 7466559
• 负责人: DONALD E INGBER
• 金额: $ 60.64万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466559
• 关键词: Adhesions; Adhesives; Adult; Apoptosis; Back; Behavior; Biomimetic Materials; Biomimetics; Cell Fate Control; Cell Shape; Cells; Chemicals; Chemistry; Clinical effectiveness; Collaborations; Complex; Development; Differentiation and Growth; Embryo; Engineering; Epithelial; Extracellular Matrix; Facility Construction Funding Category; Goals; Grant; Heart Valves; Individual; Islets of Langerhans; Laboratories; Life; Mechanics; Mediating; Mesenchymal; Mesenchyme; Molecular; Morphogenesis; Organ; Pattern Formation; Physical condensation; Process; Role; Shapes; Signal Transduction; Stem cells; Stress; Structure; System; Tissue Engineering; Tissues; Tooth structure; Traction; Variant; Work; angiogenesis; base; chemical genetics; design; directional cell; engineering design; feeding; member; organ regeneration; prototype; scaffold; self assembly

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.

该提案的主要目标（U54 联盟资助的 11 个项目中的第 6 个项目，题为“SysCODE：基于系统的 器官设计与工程联盟”）将定义工程原理和微观结构 设计标准与该联盟发现的分子蓝图相结合将使我们能够 制造具有诱导所需的适当机械和化学信号的仿生材料 器官再生。我们将定义组织细胞产生的微机械力以及组织细胞如何抵抗微机械力。 具有不同机械顺应性和内部微观结构的细胞外基质（ECM）有助于 局部影响区域组织形状转变和渐进结构重塑 复杂器官的形态发生和分层自组装。长期目标是利用体力 在制造可重新编程的多功能仿生支架方面确定的设计标准 干细胞重现器官形成。这些支架将模仿生命体的微机械特征 ECM 可以局部控制细胞命运的转换，并在空间上定向化学和粘附信号。 触发适当的发展级联。为了确定基本的设计原则，我们将分解 这种分层自组装过程分为单独的步骤或关键的“形态发生模块”，（例如， 间充质凝结、上皮出芽和折叠、细胞命运转换和上皮-间充质 转变）是牙齿发育过程中上皮-间质相互作用的基础，以及 胰岛和心脏瓣膜。相关分子调节剂和高通量 ECM 制造 将通过与该联盟其他成员的合作来获取战略。新的 该提案中发现的信息、ECM 材料和设计标准将与 开发组织和器官工程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 微观力学在空间上如何变化 发育中牙齿的形态发生形状转变，2) 确定改变的影响 内源性细胞产生的张力或对牙齿发育施加外部机械负荷， 3) 确定改变人工 ECM 的力学、结构和化学对 牙齿、胰岛和心脏瓣膜的形态发生和细胞命运转换。