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

本研究的长期目标是了解生物膜如何控制其结构完整性、动态响应和生理性能。这里我们专门研究红细胞膜，它有一个蛋白质网络偶联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混合模型来研究这种耦合结构的三维动态响应。该模型结合了我们预测的连接复合物的三维结构，透射电子显微镜显示的网络拓扑结构，以及文献中报道的蛋白质网络和脂质双分子层之间的几种相互作用。通过扩展这一三维动力学模型，提出了具体的目标来测试和建模患病红细胞膜力学。多尺度建模将包括基于分子的混合模型和基于有限元方法的完整细胞模型。模型将针对已发表的突变型人类红细胞（如溶血性球胞症和椭圆细胞症）的数据和将获得的敲除小鼠细胞的新数据进行测试。实验将包括微移液管抽吸，准静态和速率相关的测试和粘弹性本构响应与新的微流变学方法。粘弹性将与基于分子的混合模型进行比较，而细胞的变形将与完整的细胞模型进行比较。这项工作将为扩散/运输、结构可持续性和信号转导的生理机制提供新的视角，这些机制可能在纳米尺度上进一步受到网络中元素动力学的调节。这些知识可能提供分子组织和膜生物力学之间缺失的联系，并提高对血液系统疾病的理解和治疗。更广泛的影响是一个框架，以了解广泛的有趣和重要的生物膜结构和路径的仿生学合成生物膜，膜为基础的生物传感器，和其他结构。项目描述：拟议的研究将使我们了解红细胞膜的三维分子组织如何提供细胞的结构可持续性，并促进循环过程中氧气和二氧化碳的扩散/运输。这项研究也将帮助我们了解在血液学疾病中，细胞膜结构的遗传缺陷是如何导致红细胞寿命缩短的。它还将为科学家和工程师建造受生物学启发的结构奠定基础。

DESCRIPTION (provided by applicant): 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. 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.