Conformational Switch, Activation and Clustering in Cell Focal Adhesions

细胞通过连接附着在固体表面或它们所在的组织上，这种连接被称为“局部粘连”。细胞通过粘连以机械和生化的方式与环境相互作用。这在细胞和它们的组织之间产生了机械力化学耦合。这种偶联控制着细胞的许多生物学功能，如存活，细胞向另一种类型的变化，以及细胞是否可以从身体的一个部位移动到另一个部位。局部粘连是包围哺乳动物、鸟类和爬行动物细胞的膜的一部分。由于许多不同的物种(包括人类)都有局部粘连，了解它们如何传递机械力化学信号将对理解重要的生物学具有广泛的适用性。这项研究将创建计算机模型，研究焦点粘连是如何从许多分子中形成的，以及这些分子如何相互作用来传递信号。作为研究的一部分，这些计算机模型将与收集的真实数据进行测试，以确保它们是正确的。了解局部粘连的形成和功能最终将激发新型细胞医学的发展。这个项目需要几个不同的科学领域，包括生物、化学、力学和生物工程。首席研究人员还将通过创建一个包括未被充分代表的社区学院学生在内的年度研讨会来接触这些广泛分布学科的本科生，以帮助扩大对工程研究的参与。了解整合素激活、聚集以及焦点粘连的招募和成熟的详细路径将提供对细胞基质信号调节机制的洞察。虽然人们普遍认为整合素信号依赖于分子中某些点的变构构象变化，并在整个结构中传播，但导致其激活和广泛构象变化的事件序列在许多方面仍然难以捉摸。到目前为止，焦点黏附机制和整合素构象开关的动态性质阻碍了对细胞-基质黏附所涉及的关键事件的充分认识。随着计算资源和先进技术的出现，计算建模现在可以有效地用来协调表面上相互矛盾的实验观测。本研究旨在填补焦点粘连形成机制方面的知识空白。该研究小组将开发粗粒度和分子动力学模型，以了解整合素激活、构象切换和信号转导的机制。利用计算模型和体外实验，将研究不同焦点黏附蛋白的竞争和协同作用。

Cells attach to a solid surface or to the tissue they are part of by connections called "focal adhesions". The cells interact mechanically and biochemically with their environment through the adhesions. This creates a mechanochemical coupling between the cells and their tissue. The coupling controls many biological functions of the cell, such as survival, change of the cell into another type and also whether it can move from one part of the body to another. The focal adhesions are part of the membrane that surrounds the cells of mammals, birds and reptiles. Since so many different species (including humans) have focal adhesions, understanding how they transmit mechanochemical signals will have broad applicability to understanding important biology. The research will create computer models of how the focal adhesion forms from the many molecules that are part of it and how the molecules interact to transmit signals. The computer models will be tested against real data collected as part of the research to ensure that they are correct. Understanding the formation and function of focal adhesions will ultimately inspire new types of cell-based medicine. This project requires several different fields of science including biology, chemistry, mechanics, and bioengineering. The principal investigator also will reach out to undergraduate students in these broadly spread disciplines by creating an annual workshop that includes underrepresented community college students to help broaden participation in engineering research.Understanding the detailed pathways for integrin activation, clustering, and recruitment and maturation of focal adhesions will provide insight on the regulatory mechanisms of cell-matrix signaling. While it is widely established that integrin signaling is dependent upon allosteric conformational changes that initiate at certain points in the molecule and propagate over the entire structure, the sequence of events leading to its activation and extensive conformational changes remains elusive in many aspects. The dynamic nature of the focal adhesion machinery and integrin conformational switch has so far hindered a full appreciation of the key events involved in the cell-matrix adhesion. With the advent of computational resources and advanced techniques, computational modeling can now be employed effectively to reconcile apparently contradictory experimental observations. This research is aimed at filling the knowledge gap on the mechanisms of focal adhesion formation. The research team will develop coarse-grained and molecular dynamics models to understand the mechanism of integrin activation, conformational switch and signal transduction. Using computational models and in vitro experiments, the competitive and cooperative roles of different focal adhesion proteins will be investigated.