Understanding and Manipulating Mechanics-Based Collagen Synthesis to Advance Functional Biomaterials

该奖项将研究胶原蛋白的力学。 胶原蛋白是生物体中的关键结构蛋白。 它对软组织和承重器官的功能至关重要。胶原蛋白对机械负荷敏感。 即使是微小的损害也会严重损害健康或导致疾病。例如，商业胶原蛋白市场每年将很快超过60亿美元，因为人们寻求抗衰老和关节，皮肤，骨骼和肌肉健康的补充剂和治疗。重建天然胶原蛋白或设计具有功能规格的胶原蛋白的能力将满足一系列应用中未满足的需求。需求是巨大的，但满足需求所需的知识仍然有限。我们的目标是首次确定机械负荷如何促使细胞产生胶原蛋白（前体）的构建模块以及产生胶原蛋白本身。该项目将为细胞如何将机械刺激转化为生物反应提供基本的新见解。这些新知识将促进胶原蛋白的生产并改变组织工程，为使用机械加载（例如压缩）在实验室环境中驱动胶原蛋白的生产提供实用的设计原则。这项工作将为胶原蛋白相关疾病提供新的治疗方法，并为软组织损伤，疾病和畸形患者提供先进的临床治疗，从而促进国民健康。 本项目的目标是（1）确定机械应变和应力在驱动胶原蛋白产生之前的氨基酸前体代谢产生中的作用，（2）建立并验证负载诱导胶原蛋白产生的设计原则，以解锁基本理解和功能性组织工程。对接种细胞的琼脂糖样本施加精确的循环机械载荷将实现来自不同主应变和单独应力的均匀刺激。将这些实验与代谢组学通量和统计分析相结合，将建立主菌株和前体生产之间的关系。计算建模将建立主应力和代谢组学响应之间的关系。这项工作将测量在不同施加的应变/应力下VI型胶原蛋白的产生，以量化和验证能够体外合成具有特定机械性能的胶原蛋白的设计原则。这些知识的意义是双重的：它将（1）贡献关于机械刺激和胶原蛋白产生之间关系的原始基础知识;（2）为组织工程师提供工具，以生产先进的基于细胞的材料，用于软组织的功能复制。通过确定特定的应力和应变如何驱动机械转换，这项工作将改变一系列领域和翻译应用。该奖项反映了NSF的法定使命，并被认为值得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来支持。

This award will study the mechanics of collagen. Collagen is a key structural protein in living organisms. It is essential to the function of soft tissues and load-bearing organs. Collagen is sensitive to mechanical loads. Even microscopic damage can significantly undermine health or lead to disease. For example, the commercial collagen market will soon exceed $6B annually as people seek supplements and treatments for anti-aging and health of joints, skin, bone, and muscle. The ability to reconstruct native collagen or to engineer collagen with functional specifications would fulfill unmet needs across a range of applications. Demand is enormous, but the knowledge required to meet it remains limited. Our objective is to determine, for the first time, how mechanical loading prompts cells to produce the building blocks of collagen (precursors) as well as to produce collagen itself. The project will provide fundamental new insight into how cells convert mechanical stimuli into biological responses. This new knowledge will advance production of collagen and transform tissue engineering, providing practical design principles for using mechanical loading (e.g. compression) to drive the production of collagen in a laboratory setting. This work will enable novel therapies for collagen-related morbidities and advance clinical treatment for patients with soft-tissue injuries, disease, and deformities, thus advancing the national health. A comprehensive outreach plan will disseminate results to both scientists and to the general public.The objectives of this project are to (1) establish the roles of mechanical strains and stresses in driving metabolic production of the amino acid precursors that precede production of collagen and (2) establish and validate design principles for load-induced production of collagen to unlock fundamental understanding and functional tissue engineering. The application of precise, cyclic mechanical loadings to cell-seeded agarose specimens will achieve homogeneous stimulation from distinct principal strains, and separately, stresses. Combining these experiments with metabolomic flux and statistical analyses will establish relationships between principal strains and production of precursors. Computational modeling will establish relationships between principal stresses and metabolomic responses. This work will measure production of type VI collagen under different applied strains/stresses to quantify and validate design principles that enable the in vitro synthesis of collagen with specified mechanical properties. The significance of this knowledge is twofold: it will (1) contribute original, foundational knowledge on the relationships between mechanical stimuli and collagen production; and (2) provide tools for tissue engineers to produce advanced cell-based materials for functional replication of soft tissues. By establishing how specific stresses and strains drive mechanotransduction, this work will transform a range of fields and translational applications.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.