Patterns of biological damage: managing subsystem failure in cellular systems

生物损伤模式：管理细胞系统中的子系统故障

• 批准号: RGPIN-2014-06245
• 负责人: Rutenberg, Andrew
• 金额: $ 1.82万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=633310
• 关键词: Patterns; biological; damage; managing; subsystem

Biological systems eventually fail, rupture, break, or die. These systems actively avoid, repair, and manage subsystem failure during self-organized growth and development. My group will computationally model biological failure at different levels of organization from the molecular to the organism. We want to understand how living systems control spatial and temporal patterns of damage and failure, and to learn from living systems how to design and manipulate useful and resilient response to failure at the nanoscale. We will study failure across scales, from subsystem to system. For example, how molecular failure affects macromolecular mechanisms, or how organelle failure affects cellular function. We will use the theoretical tools of soft-materials, statistical, computational, and biological physics to focus on physical aspects of failure. We will pursue three directions at distinct levels of organization: collagen tissue, peroxisome number and quality control, and bacterial invasion of host cells.Type-I collagen is important for connective tissue. It is built by tropo-collagen molecules assembling into fibrils. We will develop an elastic model of collagen fibrils with both discrete fibril damage and rupture of loaded bundles of fibrils. We will also explore the energetics of tropo-collagen alignment within collagen fibrils, in order to understand when damage becomes energetically favourable. Together, we will be able to predict collagen materials properties from laboratory measurements of individual fibrils. This would allow us to efficiently explore the molecular determinants of collagen damage and failure.Peroxisomes are small metabolically-active essential organelles within cells. Unneeded and damaged peroxisomes are selectively removed by the cell through a process called autophagy. Very little is known about peroxisome damage processes, and in particular how peroxisome function is maintained by the cell in the face of continual damage. This will be the focus of our modelling. The result of our work will be to better understand how cells dynamically manage large numbers of small organelles.The invasion of a host eukaryotic cell by a bacterium involves a variety of levels: the host tissue, cells, and subcellular compartments and processes but also the removal of individual bacteria by autophagy. Cellular infective process involve cellular invasion, escape into the cytoplasm, reproduction, and transmission to adjoining cells. We will model interactions between different bacteria, and between different stages of infection in these systems. These will be complemented by more mechanistic models of the different stages of invasion. As our programmes in peroxisomes and bacterial invasion mature, they will be combined to lead to additional insight into the mechanisms of dynamic regulation of number and function of small organelles or bacteria in host cells.Progress will be accelerated with active experimental collaborations in each direction. This will let us bring interesting problems from biology into physics. We will also make physics techniques useful for biologists by connecting quantitative modelling with data driven experiments. These will help us to develop a multi-level understanding of these biological systems, by combining biological, biophysical, and modelling approaches. This will highlight physical mechanisms of cause and effect in these systems. Identifying and understanding the mechanisms behind robustly quantitative phenomenology will allow us to turn each phenomenon, and its associated phenotypes, around into tools to look deeper into how biological systems work in the face of damage.

生物系统最终会失败、破裂、断裂或死亡。这些系统在自组织生长和发展过程中主动避免、修复和管理子系统故障。我的团队将在从分子到有机体的不同组织层次上对生物学失败进行计算建模。我们希望了解生命系统如何控制空间和时间模式的损害和失败，并从生命系统中学习如何设计和操纵有用的和有弹性的反应失败在纳米级。我们将研究从子系统到系统的跨尺度故障。例如，分子故障如何影响大分子机制，或细胞器故障如何影响细胞功能。我们将使用软材料，统计，计算和生物物理学的理论工具，专注于故障的物理方面。我们将在不同的组织水平上追求三个方向：胶原组织、过氧化物酶体数量和质量控制以及宿主细胞的细菌入侵。I型胶原蛋白对结缔组织很重要。它是由原胶原蛋白分子组装成原纤维。我们将开发一个弹性模型的胶原纤维与离散纤维损伤和断裂的负载束的纤维。我们还将探讨胶原纤维内原胶原排列的能量学，以了解损伤何时变得能量有利。总之，我们将能够预测胶原蛋白材料的性能从实验室测量的个别原纤维。这将使我们能够有效地探索胶原蛋白损伤和失效的分子决定因素。过氧化物酶体是细胞内具有代谢活性的重要细胞器。不需要的和受损的过氧化物酶体被细胞通过一种称为自噬的过程选择性地清除。对过氧化物酶体损伤过程知之甚少，特别是在面对持续损伤时细胞如何维持过氧化物酶体功能。这将是我们建模的重点。我们的工作结果将是更好地了解细胞如何动态管理大量的小细胞器。细菌入侵宿主真核细胞涉及多种水平：宿主组织、细胞和亚细胞区室和过程，以及通过自噬去除单个细菌。细胞感染的过程包括细胞侵入、逃逸到细胞质、繁殖和传播到相邻细胞。我们将模拟不同细菌之间的相互作用，以及这些系统中不同感染阶段之间的相互作用。这些将由入侵不同阶段的更机械模型来补充。随着我们在过氧化物酶体和细菌入侵方面的项目的成熟，它们将结合起来，进一步深入了解宿主细胞中小细胞器或细菌的数量和功能的动态调节机制。在每个方向积极的实验合作将加速进展。这将使我们把有趣的问题从生物学带入物理学。我们还将通过将定量建模与数据驱动实验相结合，使物理技术对生物学家有用。这将有助于我们通过结合生物学、生物物理学和建模方法，对这些生物系统进行多层次的理解。这将突出这些系统中的因果物理机制。识别和理解强有力的定量现象学背后的机制将使我们能够将每种现象及其相关的表型转化为工具，以更深入地研究生物系统在面对损伤时如何工作。