Conformational Switch, Activation and Clustering in Cell Focal Adhesions

细胞焦点粘附中的构象转换、激活和聚集

• 批准号: 1538707
• 负责人: Mohammad Mofrad
• 金额: $ 44.69万
• 依托单位: University of California-Berkeley
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1538707&HistoricalAwards=false
• 关键词: Conformational; Switch; Activation; Clustering; Cell

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.

细胞通过称为“局灶性粘连”的连接附着到固体表面或它们所属的组织上。 细胞通过粘附与其环境发生机械和生物化学相互作用。 这在细胞和它们的组织之间产生了机械化学耦合。 这种耦合控制着细胞的许多生物学功能，例如生存，细胞转变为另一种类型，以及它是否可以从身体的一个部位移动到另一个部位。 粘着斑是哺乳动物、鸟类和爬行动物细胞周围膜的一部分。 由于许多不同的物种（包括人类）都有局灶性粘连，了解它们如何传递机械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，以了解粘着斑是如何从其中的许多分子中形成的，以及分子如何相互作用以传递信号。 计算机模型将与作为研究的一部分收集的真实的数据进行测试，以确保它们是正确的。 了解局灶性粘连的形成和功能将最终激发新型细胞医学。 这个项目需要几个不同的科学领域，包括生物学，化学，力学和生物工程。首席研究员还将接触到本科生在这些广泛传播的学科，通过创建一个年度研讨会，包括代表性不足的社区大学的学生，以帮助扩大参与工程研究，了解整合素激活，聚集，募集和成熟的局灶性粘连的详细途径将提供对细胞基质信号的调节机制的见解。虽然广泛确定整联蛋白信号传导依赖于在分子中的某些点处起始并在整个结构上传播的变构构象变化，但导致其活化和广泛构象变化的事件序列在许多方面仍然难以捉摸。粘着斑机制和整合素构象转换的动态性质迄今阻碍了对细胞-基质粘附中关键事件的充分理解。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调和明显矛盾的实验观察。本研究的目的是填补知识空白的机制，粘着斑的形成。研究团队将开发粗粒度和分子动力学模型，以了解整合素激活，构象转换和信号转导的机制。使用计算模型和体外实验，不同的粘着斑蛋白的竞争和合作的作用进行了研究。