Actin filaments and microtubulus

 描述（由申请人提供）：最近有报道称肌动蛋白丝和微管能够传递电信号并维持离子电导。由于电信号沿着这些细丝的速度取决于特定条件，与神经脉冲的传播范围相同，因此电信号沿着这些细丝的同时传播和电化学电流沿着轴突膜的同时传播原则上是可能的。在细胞中观察到的这种新型传导机制打开了未探索的前沿，将改变目前对神经活动和神经网络的理解。毫不奇怪，这些结构的离子传导与定向生长、细胞毒性、可塑性和迁移等多种过程有关。然而，支持这种行为的基本生物物理原理却知之甚少。因此，这项研究的目的是产生大量的初步结果，以推进微管和肌动蛋白丝的离子电导和电信号传输特性的分子理解。我们相信纤维和轴突膜可能能够传递不同种类的信息。这种能力可能以不同的方式受到年龄和生理条件的影响，因此电信号沿沿着丝和神经轴突膜的相应传播可能与不同的神经活动功能障碍有关。毫无疑问，研究这些电缆状细丝的电和溶剂化特性背后的生物物理原理可以在许多发育和退行性大脑疾病的分子原因方面取得迫切需要的进展。我们可能无法验证我们的假设，并使用传统的模型和方法来解决这一知识差距。因此，本项目的目标之一是开发一种计算工具，以合理地研究影响细胞外和细胞内环境中电信号的构象变化和电导的电生理机制。我们将在分子水平上对这些性质进行系统的表征。这一理论框架也将对生物化学的传统领域做出巨大贡献，在这些领域，静电是分子性质的主要部分。所提出的计算模型将进一步扩展，以产生数学引擎来研究蛋白质中的信号转导。该提案的结果将对非神经元信号转导的理解和临床应用产生重大影响，并可能开辟新的治疗途径，以帮助目前受这些疾病影响的数百万患者。此外，计算模型（将公开提供）将使涉及蛋白质电导的各种技术和生物医学应用的进步成为可能，如电化学生物传感器、组织生长的电刺激和生物分子处理器。

 DESCRIPTION (provided by applicant): Recently it has been reported that actin filaments and microtubules are able to transmit electric signals and sustain ionic conductance. Since the velocity of electrical signals along these filaments is, depending on specific conditions, of same range as the propagation of neural impulses, the concurrent propagation of electrical signals along these filaments and electrochemical currents along the axonal membrane is possible in principle. This novel conduction mechanism observed in cells opens unexplored frontiers that will change the current understanding of neural activities and neuronal networks. Not surprisingly, the ionic conduction of these structures has been associated with processes as diverse as directional growth, cytotoxicity, plasticity, and migration. However, the underlying biophysical principles that support this behavior are poorly understood. Therefore, the objective of this proposed research is to generate substantial preliminary results to advance the molecular understanding of ionic conductance and electric signal transmission properties of microtubules and actin filaments. We believe that filaments and axon membranes may be able to transmit different kinds of information. Such capability may be affected by age and physiological conditions in different manner and therefore the corresponding propagation of electrical signal along filaments and neural axon membrane might be associated to different neural activity dysfunctions. Without question, investigating the biophysical principles underlying the electric and solvation properties of these cable-like filaments can bring an urgently needed progress in the molecular causes of many developmental and degenerative brain disorders. We may not validate our hypothesis and address this gap in knowledge using conventional models and approaches. Therefore one of the aims of this project consists in developing a computational tool to rationally investigate the electrophysiological mechanisms that affect conformational changes and conductance of electrical signals in both extra- and intracellular environments. We will perform a systematic characterization of these properties at a molecular level. This theoretical framework would also make great contributions to conventional areas of biochemistry where electrostatics underlies a major part of molecular properties. The proposed computational model will be then further extended to produce the mathematical engine to investigate signal transduction in proteins. The outcomes of this proposal will have a significant impact on the understanding and clinical applications of non-neuronal signal transduction and could open new therapeutic avenues to help the millions of patients currently affected by these disorders. In addition, the computational model (which will be publicly available) will enable the advancement of various technological and biomedical applications involving electrical conductance in proteins such as electrochemical biosensors, electric stimulation of tissue growth, and biomolecular processors.