Collaborative Research: Molecular Mechanics Dictate the Mechanical Behavior of an Extracellular Matrix Fiber

该研究的目的是表征纤维状形式的纤连蛋白的机械性能，以及细胞外基质结构，这是必不可少的发展，并上调病理，如癌症和动脉粥样硬化，通过纤连蛋白纤维的模型系统的分析和使用的计算模型建立在纤连蛋白分子的随机特性。纤连蛋白在体内组装成具有极高延展性的独特材料，导致推测其与细胞和细胞信号分子的一连串结合位点可能由机械力驱动。该提案是独特的，因为它将量化纤连蛋白纤维的物理特性，这些物理特性定义了其在体内广泛的机械应变下的功能，并试图将这些物理特性与纤维的分子结构联系起来。该方法将利用一种用于量化模型纤维中纤连蛋白分子的分子结构的技术，该技术将与纤连蛋白纤维机械性质的计算模型进行比较，该计算模型考虑了纤连蛋白分子的分子解折叠和熵弹簧样行为。我们期望这一跨学科的建议不仅能产生对控制机械传导的潜在机制的基本理解，而且还能产生广泛的由于纤连蛋白在体内的基本作用，在再生医学和组织工程中具有广泛的意义。令人惊讶的是，尽管我们对物理环境对几乎每种研究细胞的行为的重要性有着广泛的了解，但对天然细胞外基质结构的性质却知之甚少。该计划将具有变革性，能够促进机械传导研究的新方法，并使本科生和研究生沉浸在广泛的技术创新中。将通过与女工程师协会和少数族裔工程师协会的合作关系，促进妇女和少数族裔学生的积极参与。此外，该项目将作为一个工具，为波士顿大学和康奈尔大学的课程，是针对第三年的本科生的实验室模块的发展。

The objective of the research is to characterize the mechanical properties of the fibrillar form of fibronectin, and extracellular matrix structure that is essential for development and that is upregulated in pathologies such as cancer and atherosclerosis, through the analysis of a model system of fibronectin fibers and the use of a computational model built upon the stochastic properties of fibronectin molecules. Fibronectin is assembled into a unique material in vivo with extreme extensibility, leading to speculation that its litany of binding sites for cells and cell signaling molecules may be actuated by mechanical force. This proposal is unique in that it will quantify physical properties of fibronectin fibers that define its function in vivo over a wide range of mechanical strains and attempt to connect these physical properties with the molecular architecture of the fiber. The approach will utilize a technique for quantifying the molecular structure of fibronectin molecules in model fibers that will be compared with a computational model of fibronectin fiber mechanical properties that considers both molecular unfolding and entropic spring-like behavior of fibronectin molecules.By combining all of these efforts, we expect this interdisciplinary proposal not only to generate a fundamental understanding of the underlying mechanisms governing mechanotransduction but also to have broad ranging implications in regenerative medicine and tissue engineering due to the fundamental role of fibronectin in vivo. It is surprising that despite our vast understanding of the importance of the physical environment on the behavior of virtually every studied cell, relatively little is known about the properties of native extracellular matrix structures. This program will be transformative in its capacity to promote new approaches in mechanotransduction research, as well as to immerse undergraduate and graduate students in a broad range of technological innovation. Active participation of both women and minority students will be fostered via a collaborative relationship with the Society of Women Engineers and Minority Engineers Society. Furthermore, this project will serve as a vehicle for the development of lab modules for courses at Boston University and Cornell University that are targeted for 3rd year undergraduate students.