Causes and consequences of protein aggregation in cellular degeneration – PAGDEG

In this project, we propose interdisciplinary approaches to improve our understanding of cellular degeneration in relation to aging and, in parallel, to antibiotic treatment of Escherichia coli. This bacterium is not only the best-known organism but also the simplest aging model available. We thus pursue the well-supported hypothesis that aging is a fundamental universal process of all living organisms down to bacteria. From a cellular viewpoint, aging is arguably due to the accumulation of damage over time that degenerates cellular functions thus affecting the survival of the organism. However, most aspects of aging are still elusive. For instance, genetically-identical individuals within a constant homogenous environment display different aging kinetics even in well-controlled single-cell experimental systems as bacteria and yeast. To decipher these aspects, a key will be the availability of quantitative studies of causes and consequences of specific damages accretion. More specifically, our proposal aims at understanding one of the key phenomena underlying cellular degeneracy, namely protein aggregation. We have recently demonstrated that E. coli ages through a process that is largely linked to accumulation of damaged aggregated proteins. Importantly, protein aggregation is as well a hallmark of human aging and is causal to numerous aging-related diseases of huge health and economic burden (i.e., neurodegenerative diseases as Alzheimer and Parkinson). These issues are also central in persistance to antibiotic-induced death, an alarming emerging problem in health and domesticated animal agriculture. While the latter phenomenon has been described over 60 years ago, it is only partially understood for a small subset of antibiotics (e.g. beta-lactams). Better understanding of the causes and consequences of protein aggregation in E. coli may hence lead to both new modalities of antibiotic administration as well as to new venues of research for aging and age-related disease treatments. In essence, using both quantitative experimental and theoretical approaches, our project tackles the spatio-temporal dynamics of in vivo protein aggregation at two scales: (i) the aggregation process per se and, (ii) machinery governing the process. First, protein aggregation in vivo will be follwed experimentally coupled with a diffusion-aggregation-based modeling approach. Furthermore, the dynamic changes with time of the machinery (chaperones, proteases) governing protein folding quality will be considered as a paradigm of aging and addressed both experimentally and by modeling of the underlying machinery interactions. We will also address cellular degeneration mediated by antibiotic treatment (e.g., streptomycin) that leads to aberrant protein production and aggregation, as a model of bacteria escaping antibiotic treatment and the death it should induce.To realize its objectives, our proposal intimately blends innovative experimental approaches (nanofabrication and microfluidics, image analysis and quantitative fluorescence microscopy) with simulation / modeling (individual-based simulations, continuous dynamical systems). This experimental platform that can be further expanded to other biological models is based on innovative solutions and advancements not only wih respect to the biological question at hand but also within the disciplined represented here (aplied mathematics, nanotechnology and computation).