Modelling Intracellular Transport

描述（由申请人提供）：细胞的空间组织取决于细胞内货物沿微管和肌动蛋白丝的运输。运动蛋白的动力蛋白、动力蛋白和肌球蛋白家族运输各种囊泡和细胞器，包括线粒体、核内体，甚至是进入细胞的病毒。大量的努力已经投入到了解这个运输系统的各个组成部分是如何工作的，例如，对马达的单分子研究。然而，关于运输途径中多个相互作用的组件如何产生功能，特别是多个马达如何沿着细丝运输货物以及在细丝之间切换的功能，我们知之甚少。这项研究的目的是了解细胞内转运是如何运作的以及它是如何被调节的。具体来说，我们有以下目标：目标1：确定货物上的多个电机是合作还是独立移动和分担负载。目标2：通过在交叉灯丝上的马达之间的拔河来确定开关的作用。目的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。

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.