Multiscale Models of Bacterial Chemotaxis and Phase Segregation in Axons

该项目研究两个生物系统中多尺度性质的基本问题。第一个主题涉及细胞群体的趋化性，这是细胞响应外部化学信号的定向运动。目前使用偏微分方程的细胞群体的趋化性的连续模型是现象学的，并不符合最近的实验数据。本研究在细菌趋化性的背景下研究了这个问题，并基于细胞信号传导的详细生物化学从基于细胞的模型中推导出连续模型。这项任务涉及开发新的多尺度方法，处理单细胞动力学和重叠的时间尺度的非线性。第二个主题涉及轴突细胞骨架的动力学和组织。轴突生理学的一个基本问题是了解轴突细胞骨架的结构是如何发展和维持健康的，以及它在疾病中是如何受到干扰的。本研究使用多尺度模型研究导致疾病中观察到的轴突细胞骨架分子分离的机制，并将与实验学家密切合作进行。复杂的生物系统涉及多个空间和时间尺度。要完全理解这些系统，多尺度模型和方法是必不可少的工具。本研究通过开发新的多尺度模型和方法来解决两个生物系统中多尺度性质的问题。第一个涉及响应化学信号的定向细胞运动，这在细菌诱导的感染、生物修复、伤口愈合、癌症转移和胚胎发育中至关重要。这项研究将导致细菌种群定向运动的定量机制模型。这些模型将提高我们预测和控制细菌相关感染等健康问题和生物修复等环境问题的能力。由此产生的多尺度分析框架广泛适用于研究其他类型的细胞、蚂蚁、鸟类和动物的集体运动，因此这项研究在医学和生态学方面具有深远的影响。第二个主题是关于轴突的生理学，轴突是神经细胞细长的突起。维持轴突细胞骨架的规则形状和组织对于神经元的正常功能至关重要。在健康状态下，轴突细胞骨架的正常组织是如何维持和建立的？它在神经退行性疾病中是如何受到干扰的？本研究利用整合轴突细胞骨架分子的详细生物学的多尺度模型来调查这些问题。这项研究将揭示许多神经退行性疾病的潜在机制，如肌萎缩侧索硬化症。该项目还将涉及在多尺度建模和湿实验室实验之间的接口具有不同背景的本科生和研究生的跨学科培训。

This project investigates fundamental questions of a multiscale nature in two biological systems. The first topic concerns chemotaxis of cell populations, which is the directed movement of cells in response to external chemical signals. Current continuum models for chemotaxis of cell populations using partial differential equations are phenomenological and do not match recent experimental data. This research investigates this issue in the context of bacterial chemotaxis, and derive continuum models from cell-based models based on the detailed biochemistry of cell signaling. This task involves development of new multiscale methods that deal with nonlinearities of single-cell dynamics and overlapping time scales. The second topic concerns the dynamics and organization of the axonal cytoskeleton. A fundamental question in axonal physiology is to understand how the structure of the axonal cytoskeleton is developed and maintained in health and how it gets perturbed in diseases. This research investigates the mechanisms that lead to the segregation of axonal cytoskeletal molecules observed in diseases using multiscale models, and will be conducted in close collaboration with experimentalists.Complex biological systems involve multiple space and time scales. To completely understand these systems, multiscale models and methods are essential tools. This research addresses questions of a multiscale nature in two biological systems by developing new multiscale models and methods. The first concerns the directed cell movement in response to chemical signals, which is crucial in bacteria-induced infections, bioremediation, wound healing, cancer metastasis, and embryonic development. This research will lead to quantitative, mechanistic models for directed movement of bacterial populations. These models will enhance our ability to predict and control health problems such as bacteria-associated infections and environmental problems such as bioremediation. The resulting multiscale analysis framework is broadly applicable to study collective movement of other types of cells, ants, birds and animals, and thus this research has far-reaching impacts in medicine and ecology. The second topic concerns the physiology of axons, which are long thin projections of nerve cells. Maintaining the regular shape and organization of the axonal cytoskeleton is critical for the normal functioning of neurons. How is the normal organization of the axonal cytoskeleton maintained and established in health? How is it perturbed in neurodegenerative diseases? This research investigates these questions using multiscale models that integrate the detailed biology of the axonal cytoskeletal molecules. This research will shed light on the underlying mechanisms of many neurodegenerative diseases such as amyotrophic lateral sclerosis. This project will also involve cross-disciplinary training of undergraduate and graduate students with diverse backgrounds at the interface between multiscale modeling and wet-lab experiments.