Polyelectrolyte Nature of Cytoskeleton Filaments

细胞骨架丝的聚电解质性质

基本信息

批准号：
10179425
负责人：
Marcelo Marucho
金额：
$ 37.5万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179425
关键词：
Actins Advanced Development Affect Age Algorithms Area Axon Binding Proteins Biological Biophysical Process Biophysics Biotechnology Bundling Cardiomyopathies Cell physiology Charge Code Computer software Computers Cortical Malformation Crowding Cryoelectron Microscopy Cytoskeleton Data Development Devices Dilated Cardiomyopathy Disease Electric Capacitance Electrolytes Electrostatics Environment Equilibrium F-Actin Filament Functional disorder G Actin Genes Goals Grant Growth Guanosine Triphosphate Higher Order Chromatin Structure Hypertrophic Cardiomyopathy Ions Libraries Maps Membrane Methodology Microfilaments Microtubules Modeling Molecular Molecular Structure Muscle Mutation Myopathy Nature Neurons Neurosciences Outcome Pathologic Patients Performance Physiological Play Prevention Productivity Property Protein Isoforms Radial Research Research Project Grants Research Proposals Rod Role Shapes Signal Transduction Sodium Chloride Speed Structural defect Structure Surface Techniques Testing Time Tubulin Variant Water Width base clinical application computerized tools deafness density design electric field electrical potential experience experimental study fetal frontier graphical user interface innovation light scattering malformation mutant novel novel therapeutics open source polymerization prevent prototype repaired screening skeletal theories transmission process zeta potential

项目摘要

Actin filaments (F-actin) and microtubules (MTs) are highly charged rod-like polyelectrolytes formed by polymerization of G-actin and tubulin subunits, respectively. These cytoskeleton filaments are essential for directional growth, shape, division and other important biological activities in eukaryotic cellular processes. Mutations in G-actin / tubulin genes are often evident in pathological conditions. Actin mutations may cause dilated or hypertrophic cardiomyopathies, congenital skeletal myopathies and deafness. Whereas tubulin mutations are associated with fetal malformations of cortical development. When subjected to intracellular biological environment alterations, even normal G-actin and tubulin genes are associated with dysfunctions and malformations in F-actins / Mts such as dysregulated assembly, misleading protein binding, abnormal polymerization stability, and defective electric signal transmission. The basis for cytoskeleton filaments to transmit electric signals and overcome electrostatic interactions to form bundles and networks appears primarily dominated by the polyelectrolyte nature of these filaments rather than their tertiary structures. However, the underlying biophysical principles and molecular mechanisms that support the polyelectrolyte nature of F-actin and MTs, and their properties are still poorly understood due to the lack of appropriate methodologies. In this research project an innovative approach for cytoskeleton filaments is proposed to balance accurate and efficient computational tools with experimental techniques, making it possible for the first time, to comprehensively and efficiently characterize bundling formation and electric signal propagation under the numerous intracellular environments and filament molecular structures that are usually present in normal and pathological conditions. It is hypothesized that molecular and/or cellular alterations, often evident in pathological conditions caused by age and inheritance, break down equilibrium and competition between the molecular mechanisms that dominate the bundling and conducting properties of cytoskeleton filaments in normal conditions. The overall goal of this research proposal is to determine the impact of excessive alterations in the intracellular environment and variations in the filament charge produced by isoforms and mutations on the polyelectrolyte properties of cytoskeleton filaments. The outcomes of this proposal is expected to provide an unprecedented molecular understanding on why and how age and inheritance conditions induce dysfunctions and malformation in cytoskeleton filaments. This understanding may advance the prevention and/or treatment of a variety of diseases. It may also open unexplored frontiers in neuroscience. It might elucidate whether cytoskeleton filaments and axon membranes are able to transmit different kind of information and what might be the role of electrical signal propagation along filaments in neuronal cable-like theories.

肌动蛋白丝 (F-actin) 和微管 (MT) 是由以下物质形成的高电荷棒状聚电解质：分别是G-肌动蛋白和微管蛋白亚基的聚合。这些细胞骨架丝是必不可少的用于真核细胞的定向生长、形状、分裂和其他重要的生物活性流程。 G-肌动蛋白/微管蛋白基因的突变在病理条件下通常很明显。肌动蛋白突变可能导致扩张型或肥厚型心肌病、先天性骨骼肌病和耳聋。而微管蛋白突变与胎儿皮质发育畸形有关。当细胞内生物环境发生改变时，即使是正常的G-肌动蛋白和微管蛋白基因与 F-肌动蛋白/Mts 的功能障碍和畸形有关，例如失调组装、误导性蛋白质结合、聚合稳定性异常和电信号缺陷传播。细胞骨架丝传递电信号和克服静电的基础形成束和网络的相互作用似乎主要由聚电解质性质决定这些细丝而不是它们的三级结构。然而，基本的生物物理学原理和支持 F-肌动蛋白和 MT 聚电解质性质的分子机制及其特性由于缺乏适当的方法，人们对这些问题仍然知之甚少。在这个研究项目中提出了细胞骨架丝的创新方法来平衡准确和高效具有实验技术的计算工具，首次使全面有效地表征束束形成和电信号传播正常情况下通常存在的许多细胞内环境和丝状分子结构和病理状况。据推测，分子和/或细胞的改变通常在年龄和遗传引起的病理状况，打破了之间的平衡和竞争主导细胞骨架的成束和传导特性的分子机制正常条件下的细丝。本研究计划的总体目标是确定细胞内环境的过度改变和细丝电荷的变化细胞骨架丝聚电解质特性的亚型和突变。这样做的结果该提案预计将为年龄和年龄的原因和方式提供前所未有的分子理解。遗传条件会引起细胞骨架丝的功能障碍和畸形。这了解可以促进多种疾病的预防和/或治疗。也可能会打开神经科学中未探索的前沿。它可能阐明细胞骨架丝和轴突是否膜能够传输不同类型的信息以及电的作用可能是什么类似神经元电缆的理论中的信号沿着细丝传播。