The main goal of this proposal (Project 6 of 11 of a U54 Consortium grant entitled, 'SysCODE: SystemsbasedConsortium for Organ Design and Engineering') is to define engineering principles and microstructuraldesign criteria that when combined with the molecular blueprint uncovered by this Consortium will permit usto fabricate biomimetic materials with appropriate mechanical and chemical signals necessary to induceorgan regeneration. We will define how micromechanical forces generated by tissue cells and resisted byextracellular matrices (ECMs) with different mechanical compliance and internal microstructure contributelocally to the regional tissue shape transformations and progressive structural remodeling that mediatemorphogenesis and hierarchical self assembly of complex organs. The long term goal is to use the physicaldesign criteria identified in this effort to fabricate multifunctional biomimetic scaffolds that can reprogramstem cells to recapitulate organ formation. These scaffolds will mimic the micromechanical features of livingECMs 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 downthis hierarchical self assembly process into individual steps or critical 'morphogenetic modules' ,(e.g.,mesenchyme condensation, epithelial budding and folding, cell fate switching, and epithelial-mesenchymaltransitions) that underlie epithelial-mesenchymal interactions during development of the tooth, as well aspancreatic islets and heart valves. Relevant molecular regulators and high throughput ECM fabricationstrategies will be accessed through collaboration with other members of this Consortium. The newinformation, ECM materials and design criteria discovered in this proposal will then be integrated with theother projects to develop prototype materials for tissue and organ engineering.
The specific aims i nclude: 1)To analyze how cell-generated contractile forces and ECM micromechanics vary spatially duringmorphogenetic shape transformations in the developing tooth, 2) To determine the effects of alteringendogenous 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 onmorphogenesis and cell fate switching in tooth, pancreatic islet and heart valve.
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