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Dissertation/Thesis Abstract

Mathematical Understanding of Microtubule Regulation in Eukaryotic Cell Migration
by Chen, Jianlei, Ph.D., The George Washington University, 2018, 157; 10624306
Abstract (Summary)

The interdisciplinary field of theoretical biophysics integrates knowledge from physics, biology, chemistry, mathematics, and computer science to pursue fundamental principles underlying various biological phenomena. This thesis presents our efforts in developing and applying theoretical biophysics models for studies on two important biological problems. The first problem concerns a cell’s basic ability of migration, and the second focuses on the dynamic interplay between the microtubule polymer (MT) and its End Binding protein (EB) that is vital for cell migration. Cell migration is the process that cells change their physical locations. It is closely related to various biological processes such as wound healing, immune responses, embryo development and cancer cell metastases. In the first part of this thesis, we investigated the oscillatory movement of Zyxin-depleted human fibrosarcoma: without external cues, these mutant cells exhibit distinct oscillatory migration patterns along 1-D trajectory in 3-D Extracellular Matrix (ECM), unlike wild type cells that migrate randomly. To quantitatively understand this process, we developed a reaction-transportation model based on a coarse-grained molecular picture of the process involving cell polarity factors, microtubule and intracellular mechanical stress. We successfully reproduced the periodic alternation of cell polarity, which is the key element for the cell’s oscillatory migration. We discovered two distinct oscillatory phases: the “clean phase” and the “vortex phase”, named according to the topologies of the oscillation trajectories: the clean phase exhibits fast transition between the cell polarities with relevantly short oscillation period; whereas the vortex phase exhibits vortex-like dynamics around the established leading edge in addition to the overall oscillatory trajectories. We found that the vortex-like dynamics largely elongates the oscillation period and is responsible for the observed long-range oscillatory migration of the mutant cells. Our discovery of the two oscillatory phases provides physical insights into how cells may robustly alter, meanwhile stabilize, their migration directions. Furthermore, the developed reaction-transportation model can be generalized for studies on other intracellular processes embedding active and diffusive material transportations. The second part of the thesis focused on the dynamics at the plus end of microtubule (MT). As one of the most important cytoskeletal components in eukaryotic cells, microtubule plays important roles in many intracellular processes such as trafficking vesicle, establishing cell polarity, and regulating substrate adhesion dynamics. Its polymerization dynamics is associated with many proteins, among which the End Binding protein-1 (EB1) localizes exclusively to the microtubule’s growing tip, forming a comet tail like region that is critical to help establish a local environment for other microtubule-associate proteins (MAPs) to function. Currently, there is a debate on whether EB1 molecules establish their comet tail “territory” through 1-D diffusion along the MT polymer or by associating with a structurally plastic region at the MT tip. To assess the two competing mechanisms and to achieve deeper understanding of the dynamic interplay between microtubule and EB1, we developed and implement a rule-based reaction-diffusion model. We reproduced many of the existing results, including the comet tail length, the EB1 lifetime and the effective diffusion constants. Moreover, we demonstrated that the structure plasticity of tubulin units and the diffusion of EB1 on the polymer play different yet related roles in maintaining the EB1 life cycles at the MT tip: the tubulin structural plasticity defines the platform for EB1 molecules to bind to and diffuse on; whereas the EB1 diffusion helps EB1 molecules move to the low-affinity lattice region of MT to accelerate their detachment. This rule-based modeling platform can be generalized for investigating other microtubule-associated proteins.

Indexing (document details)
Advisor: Lan, Ganhui
Commitee: El-Ghazawt, Tarek, Medsker, Larry, Peng, Weiqun, Qiu, Xiangyun, van der Horst, Alexander
School: The George Washington University
Department: Physics
School Location: United States -- District of Columbia
Source: DAI-B 79/02(E), Dissertation Abstracts International
Subjects: Physics, Biophysics
Keywords: End binding protein, Eukaryotic cell migration, Mathematical modeling, Microtubule regulation, Polarity
Publication Number: 10624306
ISBN: 978-0-355-37216-8
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