3D Dynamics of Protein Network Coupled to Lipid Bilayer in Diseased Erythocytes

6.项目总结 这项研究的长期目标是了解生物膜如何控制 它们的结构完整性、动态响应和生理性能。在这里我们 特别研究红细胞膜，它有一个蛋白质网络连接到一个 脂质双分子层。我们最近开发了一种新的基于分子的3D杂交模型 该耦合结构的动力响应。该模型包含3D配置 在我们预测的连接复合体中，通过传输揭示的网络拓扑 电子显微镜，以及蛋白质网络和脂质之间的几个相互作用 文献报道的双分子膜。通过扩展此3D动态模型，具体目标是 建议对患病的红细胞膜机械性能进行测试和建模。多个- 规模模型将包括基于分子的杂交模型和完整的细胞 用有限元方法建立模型。模型将根据发布的数据进行测试 突变的人红细胞(如溶血性球形红细胞增多症和椭圆形红细胞增多症)和新的 将为基因敲除小鼠细胞获得的数据。实验将包括微吸管 抽吸、准静态和速率相关试验与粘弹性本构关系 用新的微观流变学方法进行响应。粘弹性将与 基于分子的杂交模型，同时对细胞的变形情况进行比较 完整的细胞模型。这项工作将为生理学带来新的曙光 扩散/运输、结构可持续性和信号传递的机制 转导可以由网络中的元件的动力学进一步调节 在纳米尺度上。这一知识可能提供了分子之间缺失的联系 膜的组织和生物力学，并提高对膜的认识和 血液病的治疗。更广泛的影响是一个框架，可以理解 一大类有趣和重要的生物膜结构和路径 生物仿生学在合成生物膜、膜生物传感器等方面的应用 结构。7.项目叙事 拟议中的研究将使我们能够理解三维分子是如何 红细胞膜的组织提供了细胞的结构可持续性和 促进氧气和二氧化碳在循环过程中的扩散/运输。这项研究将 也有助于我们理解膜结构中的遗传缺陷如何导致更短的 红细胞在血液病中的生命。它还将为科学家和 工程师建造以生物为灵感的结构。

6. Project Summary The long term goal of this study is to understand how biological membranes control their structural integrity, dynamical response, and physiological performance. Here we specifically study the erythrocyte membrane which has a protein network coupled to a lipid bilayer. We recently developed a new molecular-based hybrid model for the 3D dynamic response of this coupled structure. The model incorporates a 3D configuration of the junctional complex we predicted, the network topology revealed by transmission electron microscopy, and several interactions between the protein network and the lipid bilayer reported in literatures. By extending this 3D dynamic model, specific aims are proposed to test and model diseased erythrocyte membrane mechanics. The multiple- scale modeling will include the molecular-based hybrid model and a complete cell model with a Finite-Element Method. Models will be tested against published data on mutant human erythrocytes (e.g. hemolytic spherocytosis and elliptocytosis) and new data to be obtained for knockout mouse cells. Experiments will include micropipette aspiration, quasi-static and rate dependent testing and viscoelastic constitutive response with novel microrheology methods. The viscoelasticity will be compared with the molecular-based hybrid model, while the deformation of the cell will be compared with the complete cell model. This work will shed new light into physiological mechanisms by which diffusion/transport, structural sustainability, and signal transduction may be further regulated by the dynamics of the elements in the network at the nano-scale. This knowledge may provide the missing link between molecular organization and biomechanics of the membrane, and improve the understanding and treatment of hematological disorders. The broader impact is a framework to understand a wide class of interesting and important biological membrane structures and paths for biomimetics in synthetic bio-membranes, membrane-based bio-sensors, and other structures. 7. Project Narrative The proposed research will allow us to understand how the three-dimensional molecular organization of the red blood cell membrane provides structural sustainability of the cells and facilitates the diffusion/transport of oxygen and carbon dioxide during circulation. This study will also help us understand how genetic defects in the membrane structure may result in shorter life of red blood cells in hematological disorders. It will also lay a foundation for scientists and engineers to build biologically-inspired structures.