Polyelectrolyte Nature of Cytoskeleton Filaments

肌动蛋白丝（F-肌动蛋白）和微管（MT）是高度带电的棒状聚电解质， 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 在真核细胞中定向生长、成形、分裂和其他重要的生物学活动 流程. G-肌动蛋白/微管蛋白基因的突变通常在病理条件下是明显的。肌动蛋白 突变可能会导致扩张性或肥大性心肌病、先天性骨骼肌病， 耳聋而微管蛋白突变与胎儿皮质发育畸形有关。 当受到细胞内生物环境的改变时，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的功能障碍和畸形相关，如失调 组装、误导性蛋白质结合、异常聚合稳定性和缺陷电信号 传输细胞骨架细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 而不是它们的三级结构。然而，基本的生物物理原理和 支持F-肌动蛋白和MT的生物学性质的分子机制，以及它们的性质 由于缺乏适当的方法，人们对这些问题的认识仍然很少。在这个研究项目中， 提出了细胞骨架细丝的创新方法，以平衡准确和高效 计算工具与实验技术，使之成为可能的第一次， 全面、有效地表征集束形成和电信号在 许多细胞内环境和细丝分子结构，通常存在于正常细胞中， 和病理条件。据推测，分子和/或细胞的变化，往往是明显的，在 由年龄和遗传引起的病态，打破平衡和竞争之间 控制细胞骨架成束和传导特性的分子机制 在正常情况下的纤维。本研究提案的总体目标是确定 细胞内环境的过度改变和由细胞外基质产生的细丝电荷的变化 同种型和突变对细胞骨架细丝的生物学特性的影响。这个结果 这项提案有望提供一个前所未有的分子理解，为什么和如何年龄和 遗传条件诱导细胞骨架细丝功能障碍和畸形。这 理解可以促进各种疾病的预防和/或治疗。它还可以打开 神经科学中尚未探索的前沿领域这可能阐明细胞骨架细丝和轴突是否 膜能够传递不同种类的信息， 神经元电缆理论中信号沿着细丝传播。

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.