Modelling Intracellular Transport

描述(申请人提供)：细胞的空间组织依赖于细胞内货物沿微管和肌动蛋白细丝的运输。运动蛋白、动力蛋白和肌球蛋白家族的马达蛋白运输不同的囊泡和细胞器，包括线粒体、内小体，甚至进入细胞的病毒。为了了解这种运输系统的各个组成部分是如何工作的，人们付出了大量的努力，例如，对马达的单分子研究。然而，对于运输途径的多个相互作用的组成部分是如何发挥作用的，特别是多个马达如何沿着细丝运送货物和在细丝之间切换的功能，人们知之甚少。这项拟议的研究的目标是了解细胞内运输是如何运作的，以及它是如何被调控的。具体来说，我们有以下目标：7目标1：确定货物上的多个马达是协同还是独立地移动和分担负载。7目标2：确定通过交叉细丝上的电机之间的拔河切换所起的作用。7目标3：确定与细丝结合的蛋白质是否调节细丝之间的转换。我们将使用蒙特卡罗模拟来解释定量实验的结果。 与公众健康相关：细胞内的组织是通过一个运输系统维持的，在这个运输系统中，分子马达将货物从一个地方运送到另一个地方。这一运输系统的崩溃与帕金森氏病和阿尔茨海默氏症等神经退行性疾病有关，而鞭毛内运输的中断可导致多囊肾病、失明(视网膜色素变性)和发育缺陷，如器官错位在身体的错误一侧。更好地了解基本的细胞内转运过程将有助于设计新的治疗方法。

DESCRIPTION (provided by applicant): The spatial organization of the cell depends upon intracellular trafficking of cargos along microtubules and actin filaments. The kinesin, dynein, and myosin families of motor proteins transport diverse vesicles and organelles including mitochondria, endosomes, and even viruses that have entered the cell. A great deal of effort has gone into understanding how individual components of this transportation system work, e.g., single molecule studies of motors. However, little is known about how function emerges from multiple interacting components of the transport pathway, especially how multiple motors function both to haul cargos along filaments, and to switch between filaments. The goal of the proposed research is to understand how intracellular transport operates and how it is regulated. In particular we have the following aims: 7 Aim 1: : Determine whether multiple motors on a cargo move and share load cooperatively or independently. 7 Aim 2: Determine the role of switching via a tug of war between the motors on intersecting filaments. 7 Aim 3: Determine whether proteins that bind to filaments regulate switching between filaments. We will interpret the results of quantitative experiments using Monte Carlo simulations. Relevance to public health: The organization inside a cell is maintained through a transportation system in which molecular motors haul cargo from one place to another. The breakdown of this transportation system has been associated with neurodegenerative diseases such as Parkinson's disease and Alzheimers, while disruption of intraflagellar transport can lead to polycystic kidney disease, blindness (retinitis pigmentosum), and developmental defects such as Situs Inversus where organs are misplaced on the wrong side of the body. A better understanding of fundamental intracellular transport processes will aid in the design of new therapeutic approaches.