Striking a balance: mapping the structural stability and mechanical and chemical responsiveness of collagen proteins

多细胞生命由维持细胞在所需位置和组织中的结构搭建而成。传统上，这些支架被视为在发育过程中放置的坚硬、不变的支架，除非受到伤害或疾病的影响，否则不会改变。相反，最近的科学进展表明，这些细胞外支架是高度动态的，对局部微环境的变化做出反应，并将这些变化传达给它们支持的细胞，细胞反过来修改这些支架以适应变化的环境。在人类(以及所有多细胞动物)中，这些支架的主要成分是一种名为胶原蛋白的蛋白质(源自法语中的coler或to glue)。在其最小的(分子)水平上，这种蛋白质具有独特的三螺旋结构，三条链相互缠绕，形成一个长的右手螺旋。胶原蛋白在细胞内合成，然后在细胞外组装成各种高阶结构，形成环境特定的支架，支持多种功能。例如，胶原蛋白形成肌腱的绳状结构，类似的组织模板骨骼的矿化；它们也可以形成网络，支持我们组织外围的细胞，将“内”和“外”分开，以及形成肾脏的过滤屏障。迅速发展的机械生物学领域正在证明细胞对其细胞外环境的机械反应；例如，当干细胞生长在坚硬的表面上而不是柔软的表面时，干细胞分化成骨而不是脂肪细胞。目前尚不清楚的是，细胞外环境如何将这些信息传递给细胞。由于胶原蛋白(占我们体内蛋白质的1/4以上)占主导地位，我们的目标是了解胶原蛋白如何感知和传达其局部环境中的机械和化学变化。我的研究小组开发了国际上独一无二的胶原蛋白表征技术，使我们能够探索单个胶原蛋白的机械特性。我们通过结合单分子成像(使用原子力显微镜技术)和单分子力谱(使用一种新的离心力显微镜技术)来完成这项工作。我们的目标是了解胶原蛋白三螺旋长度上的序列可变性如何用于传达化学环境(例如，在细胞分泌期间或在生物过程中，如骨骼降解和癌症转移)和机械应变(例如，在我们采取的每一步或细胞拖拽其细胞外基质时发生)的变化。我的研究组的学生在物理和生物学的界面上获得实验专业知识，在不同的研究团队中发展沟通技能，并有机会在机械生物学和生物物理学领域建立国际领先地位。

Multicellular life is scaffolded by structures that maintain cells in the desired locations and organizations. Conventionally these scaffolds are viewed as rigid, unchanging supports laid down during development and unaltered except by injury or disease. Recent scientific advances are revealing instead that these extracellular scaffolds are highly dynamic, responsive to changes in their local microenvironment and communicating these changes to the cells they support, which in turn modify these scaffolds to adapt to their changed environment. In humans (and all multicellular animals), the main component of these scaffolds is a protein called collagen (from the French "coller" or to glue). At its smallest (molecular) level, this protein has a unique triple helix structure, with three chains twisting around each other to make a long, right-handed helix. Collagen proteins are made inside cells, then assemble into a wide variety of higher-order structures outside cells to form environment-specific scaffolds supporting a diversity of function. For example, collagens form the rope-like structure of tendon, with similar organizations templating the mineralization of bone; they alternatively can form networks that support cells at the periphery of our tissues, separating "inside" from "outside", and networks that form the filtration barrier of the kidney. The rapidly expanding field of mechanobiology is demonstrating that cells respond to the mechanics of their extracellular environment; for example stem cells differentiate into bone vs. fat cells when grown on a stiff vs. soft surface. What is not clear is how the extracellular environment communicates this information to cells. Because of the predominance of collagen (more than ¼ of the protein in our bodies), we aim to understand how collagen senses and communicates mechanical and chemical changes in its local environment. My research group has developed internationally unique skills in collagen characterization, which enable us to probe the mechanical properties of individual collagen proteins. We do this by a combination of single-molecule imaging (using the technique of atomic force microscopy) and single-molecule force spectroscopy (using a new technique of centrifuge force microscopy). We aim to understand how the sequence variability along the length of collagen's triple helix is used to communicate changes in chemical environment (occurring, for example, during secretion from the cell or in biological processes such as bone degradation and cancer metastasis) and mechanical strain (occurring, for example, with every step we take or by cells tugging at their extracellular matrix). Students in my research group gain experimental expertise at the interface of physics and biology, develop communication skills within a diverse research team, and have the opportunity to build international leadership in the fields of mechanobiology and biophysics.