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

这项研究的目的是通过分析纤维连接蛋白纤维的模型系统和使用基于纤维连接蛋白分子的随机性质建立的计算模型来表征纤维连接蛋白的力学性质以及在癌症和动脉粥样硬化等病理中上调的对发育至关重要的细胞外基质结构。纤维连接蛋白在体内被组装成一种独特的材料，具有极高的延伸性，这导致人们猜测，它与细胞和细胞信号分子的一系列结合部位可能是由机械力驱动的。这项提议的独特之处在于，它将量化纤维连接蛋白纤维的物理属性，这些物理属性定义了它在体内各种机械应变下的功能，并试图将这些物理属性与纤维的分子结构联系起来。该方法将利用一种技术来量化模型纤维中纤维连接蛋白分子的分子结构，并将其与纤维连接蛋白纤维力学性能的计算模型进行比较，该计算模型同时考虑了纤维连接蛋白分子的分子展开和熵弹簧行为。通过结合所有这些努力，我们预计这一跨学科的建议不仅能从根本上理解机械转导的潜在机制，而且由于纤维连接蛋白在体内的基础作用，还将在再生医学和组织工程中产生广泛的影响。令人惊讶的是，尽管我们对物理环境对几乎每个被研究细胞的行为的重要性都有广泛的了解，但对天然细胞外基质结构的性质知之甚少。该计划将具有变革性的能力，促进机械传递研究的新方法，以及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民族工程师协会的合作关系，培养妇女和少数族裔学生的积极参与。此外，该项目将作为开发波士顿大学和康奈尔大学针对三年级本科生的课程的实验模块的工具。

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.