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

患病红细胞中与脂质双层耦合的蛋白质网络的 3D 动力学

• 批准号: 7655426
• 负责人: Qiang Zhu
• 金额: $ 27.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655426
• 关键词: Accounting; Actins; Address; Adopted; Affect; Algorithms; Ankyrins; Architecture; Arts; Behavior; Bio-Base; Biological; Biomechanics; Biomimetics; Blood Circulation; Blood capillaries; Carbon Dioxide; Cell membrane; Cell model; Cells; Cereals; Chemistry; Complex; Coupled; Coupling; Data; Defect; Development; Devices; Diffusion; Disease; Elements; Elliptocytosis found; Engineering; Erythrocyte Anion Exchange Protein 1; Erythrocyte Membrane; Erythrocytes; Foundations; Functional disorder; Glycophorin; Goals; Hand; Head; Hematological Disease; Hereditary Elliptocytosis; Hereditary Spherocytosis; Human; Human body; Hybrids; In complete remission; Indium; Inherited; Interdisciplinary Study; Investigation; Ions; Joints; Knock-out; Knockout Mice; Knowledge; Life; Light; Link; Lipid Bilayers; Lipids; Liquid substance; Literature; Longevity; Measurement; Mechanics; Membrane; Membrane Proteins; Methods; Modeling; Molecular; Molecular Conformation; Molecular Structure; Mutant Strains Mice; Mutation; Non-linear Models; Oceans; Performance; Peripheral; Physiological; Play; Property; Protein Dynamics; Proteins; Publishing; Quantum Dots; Reporting; Research; Rheology; Role; Science; Scientist; Shapes; Signal Transduction; Simulate; Skeleton; Spectrin; Structure; Suspension substance; Suspensions; Techniques; Testing; Time; Transmission Electron Microscopy; Transport Process; Work; base; capillary; design; dimer; flexibility; improved; interest; mechanical behavior; membrane skeleton; multi-scale modeling; mutant; nanoscale; novel; oxygen transport; particle; protein 4.1; research study; response; sensor; simulation; skeletal; southeast Asian; three dimensional structure; three-dimensional modeling; viscoelasticity

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.

描述（由申请人提供）：项目摘要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。在这里，我们专门研究红细胞膜，它有一个蛋白质网络耦合到脂质双层。我们最近开发了一种新的基于分子的混合模型，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3D构型，透射电子显微镜揭示的网络拓扑结构，以及文献报道的蛋白质网络和脂质双层之间的几种相互作用。通过扩展这个三维动态模型，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具有微元方法的完整细胞模型。将根据突变型人红细胞（例如溶血性球形红细胞增多症和椭圆形红细胞增多症）的已发表数据和敲除小鼠细胞获得的新数据对模型进行检测。实验将包括微管抽吸，准静态和速率相关的测试和粘弹性本构响应与新的微观流变学方法。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细胞模型进行比较。这项工作将揭示新的生理机制，扩散/运输，结构的可持续性和信号转导可能会进一步调节网络中的元素在纳米尺度上的动态。这些知识可以提供膜的分子组织和生物力学之间的缺失环节，并改善血液疾病的理解和治疗。更广泛的影响是一个框架，以了解广泛的一类有趣和重要的生物膜结构和合成生物膜，基于膜的生物传感器和其他结构中的仿生路径。项目叙述：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。这项研究还将帮助我们了解膜结构中的遗传缺陷如何导致血液疾病中红细胞的寿命缩短。它还将为科学家和工程师建造生物启发的结构奠定基础。