CAREER: Mechanobiology of Mesenchymal-Epithelial Transition

当细胞之间的连接很弱时，它们就能迁移。这种情况发生在癌症扩散的时候，也发生在胚胎生长的时候。细胞能否从移动的细胞转变为留在原地的细胞，部分取决于组织的硬度。如果我们更好地了解细胞的这种变化，它将提高我们对癌症如何发展和器官如何生长的理解。从移动细胞到静止细胞的转变称为间充质-上皮转化（MET）。MET对肾脏和心脏发育、伤口愈合和癌症转移很重要。当MET发生时，迁移的细胞发生变化，使它们无法移动，并与邻近细胞紧密结合。MET取决于组织刚度，但这种依赖的细节尚不清楚。这个教师早期职业发展计划（Career）项目将测量细胞对基质刚度动态变化的反应，并确定EMT如何受到组织刚度的影响。这将有助于理解胚胎如何生长，如何更好地制造人造组织，以及构建可用于药物发现研究的“芯片上的器官”。通过该项目支持的PI和研究生将为6-12年级的教师开发和实施一个以生物力学和机械生物学概念为重点的研讨会，以便他们能够更好地教授学生，包括工程研究如何影响社会。间充质-上皮转化（MET）是一种表型变化，在这种表型变化中，具有弱细胞间接触的迁移细胞转变为具有顶基极性的紧密结合细胞。MET在胚胎重塑、器官结构建立、伤口愈合、体细胞重编程为诱导多能干细胞和癌细胞转移传播中起着核心作用。虽然人们认识到细胞生态位的机械特性在体内MET相关过程中是动态变化的，但关于微环境物理特性如何调节MET的重要问题仍然存在。CAREER项目的目标是开发一种动态水凝胶系统，该系统可以概括met相关事件期间组织力学特性的变化，然后使用该系统确定与上皮和间充质表型、细胞骨架重塑和细胞迁移相关的基因表达。进一步的研究将阐明关键的机械反应信号分子和表观遗传重塑在调节MET对机械信号的反应中的作用。将组织力学和MET联系起来的分子机制的建立将有助于更好地理解机械转导过程，并将为机械信号如何调节细胞可塑性提供见解。该研究项目为教育和推广工作提供了基础，旨在将工程和机械生物学对社会的积极影响纳入工程课程和针对6-12年级到研究生水平学生的招聘工作中。将为6-12年级的教师举办一个以生物力学和机械生物学概念为重点的研讨会，并将展示研究如何影响社会。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

When cells are weakly attached to each other, they are able to migrate. This happens when cancer spreads, but also when an embryo grows. Whether cells can change from ones that move into ones that remain in the same place is partly dependent on the tissue stiffness. If we better understand this change in cells, it will improve our understanding of how cancer progresses and how our organs grow. The change from mobile to a static cells is call mesenchymal-epithelial transition (MET). MET is important to kidney and heart development, wound healing and cancer metastasis. When MET happens, migrating cells change so that they are immobile and tightly bound to neighboring cells. MET depends on tissue stiffness, but the details of the dependence aren't known. This Faculty Early Career Development Program (CAREER) project will measure the response of cells to dynamic changes in matrix stiffness and determine how EMT is affected by tissue stiffness. This will help in understanding how embryos grow, how to better manufacture artificial tissues and in building 'organs on a chip' that can be used for drug discovery research. The PI and graduate student supported through this project will develop and implement a workshop for grade 6-12 teachers focused on biomechanics and mechanobiology concepts so that they can better teach their students, including how engineering research impacts society. Mesenchymal-epithelial transition (MET) is a phenotypic change in which migratory cells with weak cell-cell contacts transition to tightly bound cells exhibiting apical-basal polarity. MET is central to embryonic remodeling, establishment of organ architecture, wound healing, reprogramming of somatic cells into induced pluripotent stem cells, and metastatic dissemination of cancer cells. While it is recognized that mechanical properties of the cellular niche change dynamically during MET-associated processes in vivo, important questions still remain regarding how microenvironmental physical properties regulate MET. The goal of this CAREER project is to develop a dynamic hydrogel system that recapitulates changes in tissue mechanical properties during MET-associated events, and then to use this system to determine the expression of genes associated with epithelial and mesenchymal phenotypes, cytoskeletal remodeling, and cell migration. Further studies will elucidate the role of key mechanoresponsive signaling molecules and epigenetic remodeling in regulating MET response to mechanical signals. The establishment of molecular mechanisms linking tissue mechanics and MET will result in a better understanding of mechanotransduction processes and will provide insight into how mechanical signals regulate cell plasticity. The research program provides the foundation for educational and outreach efforts aimed toward incorporating positive themes about the impact of engineering and mechanobiology on society into engineering curricula and into recruitment efforts directed toward grade 6-12 through graduate-level students. A workshop for grade 6-12 teachers focused on biomechanics and mechanobiology concepts will be developed and implemented and will demonstrate how research impacts society.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.