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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=612116
• 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.

生物系统最终会失效、破裂、破裂或死亡。这些系统在自组织增长和发展过程中主动避免、修复和管理子系统故障。我的团队将对从分子到生物体的不同组织水平上的生物失败进行计算模拟。我们想要了解生命系统如何控制损伤和故障的空间和时间模式，并从生命系统中学习如何在纳米尺度上设计和操作有用的和有弹性的故障响应。我们将研究不同规模的故障，从一个子系统到另一个系统。例如，分子故障如何影响大分子机制，或者细胞器故障如何影响细胞功能。我们将使用软材料、统计、计算和生物物理的理论工具来关注故障的物理方面。我们将在不同的组织水平上追求三个方向：胶原组织、过氧化物酶体数和质量控制以及宿主细胞的细菌入侵。 I型胶原对结缔组织很重要。它是由Tropo-胶原蛋白分子组装成纤维形成的。我们将建立一个胶原纤维的弹性模型，既有离散的纤维损伤，也有加载的纤维束断裂。我们还将探索胶原纤维内对位胶原蛋白排列的能量学，以了解何时损伤变得有利于能量。在一起，我们将能够通过实验室测量单个纤维来预测胶原蛋白材料的特性。这将使我们能够有效地探索胶原损伤和失败的分子决定因素。 过氧化物体是细胞内具有代谢活性的重要小细胞器。细胞通过一种称为自噬的过程选择性地清除不需要的和受损的过氧酶体。人们对过氧化物体的损伤过程知之甚少，尤其是在面临持续损伤的情况下，细胞如何维持过氧化物体的功能。这将是我们建模的重点。我们工作的结果将是更好地理解细胞如何动态地管理大量的小细胞器。 细菌对宿主真核细胞的入侵涉及多个层面：宿主组织、细胞、亚细胞隔间和过程，但也包括通过自噬去除单个细菌。细胞感染过程包括细胞入侵、逃逸到细胞质、繁殖和传播到相邻细胞。我们将对这些系统中不同细菌之间以及感染不同阶段之间的相互作用进行建模。这些将得到入侵不同阶段的更多机械性模型的补充。随着我们在过氧化体和细菌入侵方面的计划成熟，它们将结合在一起，以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。 随着在每个方向上积极的实验合作，进展将会加快。这将使我们把生物学中有趣的问题带入物理学。我们还将通过将定量建模与数据驱动的实验相结合，使物理技术对生物学家有用。这些将有助于我们通过结合生物学、生物物理学和建模方法来发展对这些生物系统的多层次理解。这将突出这些系统中因果的物理机制。识别和理解强有力的量化现象学背后的机制将使我们能够将每一种现象及其相关的表型转化为工具，更深入地研究生物系统在面临损害时是如何工作的。