Spatiotemporal mechanical inhomogeneities in the embryonic oral epithelium and mesenchyme lead to tooth invagination

项目摘要-摘要 成人牙齿脱落是影响大多数美国人的牙齿疾病或损伤的不良后果。 因此，了解它已成为生物工程师和再生医学科学家的目标和挑战 自然组织结构生长和形成的基本原理，并应用这些知识来重建 口腔结构。1更好地了解胚胎牙齿如何发育，特别是在牙齿的早期阶段 形成（基板组织和上皮内陷的起始）是至关重要的。这个的主要目标 这项研究的目的是了解胚胎小鼠切牙牙胚发育的机制。 虽然生化信号启动基板形成和位置的过程已被充分描述，2 关于物理线索的时空模式，如细胞产生的力和组织， 弹性，影响牙胚内陷。 假设：细胞张力和组织硬度的空间定义差异（数十微米量级） 驱动上皮内陷过程。该项目的主要创新将是尖端的机械 测量技术，我将开发和应用功能理解机械的贡献， 牙胚形成我将首先确定上皮力产生在驱动上皮细胞中的功能作用， 内陷其次，我将确定间充质机械上皮内陷的贡献。和 第三，我将建立一个小鼠下颌骨在切牙区的体外模型，以研究 机械和可溶性化学线索对上皮内陷的影响。实现这些目标将使我能够 确定发育中的牙胚的力学，牙胚的力学特性如何影响和 受信号通路的影响，以及这种相互作用如何促进内陷过程。总之，这些 实验将为开发再生医学和组织工程策略奠定基础， 功能性牙齿 这个奖学金培训计划和研究培训的环境将促进我的 作为一名年轻科学家的成长，以及作为一名独立调查员的职业道路。我打算发展我的技能， 基础和分子生物学。来自化学和物理科学，这种奖学金的经验， 将让我沉浸在一个新的环境中，与那些技能与我截然不同的人在一起。 我将打造一个新的，多学科的研究方向，并扩大我独特的研究工具箱。我相信这 我将有最好的机会研究生物学和固体力学之间的联系。的这种组合 研究所，赞助商和项目将加强我作为一个独立研究员和跨领域领导者的培训， 部门调查。

Project Summary-Abstract Adult tooth loss is an undesirable consequence of dental disease or injury that affects a majority of Americans. Thus, it has become the aim and challenge of bioengineers and regenerative medicine scientists to understand the fundamental principles by which native tissue structures grow and form, and apply this knowledge to recreate oral structures.1 A better understanding of how embryonic teeth develop, especially at early stages of tooth formation (placode organization and initiation of epithelial invagination), is paramount. The primary goal of this proposal is to understand the mechanisms behind the development of embryonic mouse incisor tooth germs. While the process by which biochemical signaling initiates placode formation and position is well described,2 much less is known about how spatiotemporal patterns of physical cues, such as cell-generated forces and tissue elastic properties, influence tooth germ invagination. Hypothesis: Spatially-defined differences in cell tension and tissue stiffness (on the order of tens of microns) drive the epithelial invagination process. The main innovation of this project will be the cutting edge mechanical measurement techniques that I will develop and apply to functionally understand mechanical contributions to tooth germ formation. I will first determine the functional role of epithelial force generation in driving epithelial invagination. Second, I will determine the mesenchyme mechanical contribution on epithelial invagination. And third, I will create an in vitro model of the mouse mandible at the incisor region to examine the interplay between mechanical and soluble chemical cues on epithelial invagination. Accomplishing these aims will allow me to ascertain the mechanics of the developing tooth germ, how mechanical properties of the germ affect and are affected by signaling pathways, and how this interplay contributes to the invagination process. Altogether, these experiments will lay the groundwork to develop regenerative medicine and tissue engineering strategies to grow a functional tooth. This fellowship training plan and the environment in which the research training will take place will foster my growth as a young scientist, and career path as an independent investigator. I intend to develop my skills in fundamental and molecular biology. Coming from the chemical and physical sciences, this fellowship experience will allow me to immerse myself in a new environment with people whose skillset is very different than my own. I will forge a new, multidisciplinary research direction and expand my unique research toolbox. I believe this opportunity will best allow me to study the interface between biology and solid mechanics. This combination of institute, sponsors, and project will enhance my training as an independent researcher and field leader in cross- sector investigations.