Micromechanics and the Role of Cellular Forces, Collagen Production, and Mechanochemistry in Extracellular Matrix Growth and Remodeling

人体的软组织由生活在大蛋白质和其他生物分子基质中的细胞组成。基质的机械行为对组织和器官的功能非常重要。 基质的机械性能由蛋白质胶原形成的复杂结构控制。然而，胶原蛋白结构可以响应于机械力而改变，例如在运动期间或作为疾病进展的一部分发生的机械力。该项目将数学建模与模型组织系统的实验相结合，以研究胶原蛋白结构在外部施加的力和细胞施加的力下如何变化。 从这个项目中获得的新的理解将推进胶原生物力学和细胞机械生物学的知识。 这将通过转化为疾病研究，并通过使新的治疗策略能够解决组织结构的病理变化，来促进国家的健康和福利。该项目的一个重要成果将是为研究生和本科生提供跨学科研究培训，为他们在学术界和工业界的职业生涯做好准备。该项目还将为巴尔的摩市高中学生提供研究实习机会，这将有助于增加工程和科学技术劳动力的多样性。该项目是一个综合的微机械实验和建模计划，旨在研究胶原机械化学，机械敏感细胞收缩和机械敏感胶原蛋白生产对细胞外基质生长和重塑的作用和相互作用。该项目将（i）开发一个微组织实验系统，以测量整体机械刺激对生长和重塑的影响以及机械化学对胶原结构的影响;（ii）基于胶原沉积和降解的纤维水平过程，包括机械化学和细胞收缩的影响，开发胶原组织生长和重塑的微力学模型;和（iii）研究细胞尺度扰动对胶原生长和重塑的影响。 集成的建模和实验框架将允许单独表征胶原机械化学、胶原产生和细胞收缩的机械刺激，并评估其对组织生长、胶原结构和组织性质的重塑以及体内平衡的长期影响。 局部微扰研究将研究胶原纤维结构和细胞肌动蛋白应力纤维结构的重塑之间复杂的相互作用。 从这个项目中获得的新的基本认识将导致开发更多的胶原蛋白生长和重塑的机制和预测模型，这些模型将在机械相关疾病的研究和组织工程中得到应用。这个奖项反映了NSF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。

Soft tissues in the human body consist of cells living in a matrix of large proteins and other biomolecules. The mechanical behavior of the matrix is important to how tissues and organs function. The mechanical properties of the matrix are governed by complex structures formed by the protein collagen. However, collagen structures can change in response to mechanical forces, such as those that occur during exercise or as part of disease progression. This project combines mathematical modeling with experiments on a model tissue system to study how collagen structures change under externally applied forces and forces exerted by the cells. The new understanding gained from this project will advance knowledge of collagen biomechanics and cell mechanobiology. This will advance the nation’s health and welfare through translation to the study of diseases, and by enabling new therapeutic strategies to address pathological changes in tissue structure. An important outcome of the project will be interdisciplinary research training for graduate students and undergraduates to prepare them for careers in academia and industry. The project will also provide research internships for Baltimore City high school students that will help increase of diversity in the technical workforce in engineering and science.This project is an integrated micromechanical experimental and modeling program to investigate the role and interactions of collagen mechanochemistry, mechanosensitive cellular contraction, and mechanosensitive collagen production on the growth and remodeling of the extracellular matrix. The project will (i) develop a microtissue experimental system to measure the effects of global mechanical stimuli on growth and remodeling as well as mechanochemical effects on collagen structure; (ii) develop a micromechanical model for collagen tissue growth and remodeling based on the fibril-level processes of concurrent collagen deposition and degradation including effects of mechanochemistry and cellular contraction; and (iii) investigate effects of cell-scale perturbations on collagen growth and remodeling. The integrated modeling and experimental framework will allow separate characterization of mechanical stimulation of collagen mechanochemistry, collagen production, and cellular contraction, and evaluation of their long-term effects on tissue growth, remodeling of collagen structure and tissue properties, and homeostasis. The local perturbation studies will examine the complicated interplay between the remodeling of collagen fiber structures and cellular actin stress fiber structures. New fundamental understanding gained from this project will lead to the development of more mechanistic and predictive models for collagen growth and remodeling that will find application in both the study of mechanically implicated diseases and in tissue engineering.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.