NICHE

Network for Integrated Cellular Homeostasis

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 Obiettivo del progetto (Objective)

'There is a need for greater understanding of integrated cellular physiology to exploit cells and to tailor their activities to optimise microbial productivity in synthetic circuits and to limit microbial activity in food and pharmaceutical products. Understanding the integration of the cellular metabolic processes is fundamental to developing and exploiting cells. We have assembled a team of internationally renowned academic and industrial partners to form a training network comprising experimentalists and modellers. The partners will work synergistically to generate a cohort of well-trained young scientists with multidisciplinary skills to drive this research field forward and provide novel tools for academic and industrial research.

Our focus in this training programme is a thorough understanding of cytoplasmic homeostasis, because this is integral to the functioning of individual components and whole pathways. Cytoplasmic homeostasis is amenable to both experimentation and modelling and has profound implications for the core processes of life and productivity.

The research objectives are: • To advance our understanding of the homeostatic mechanisms of bacteria via predictive modelling and state-of-the-art experimental approaches. • To generate deep insights into effects of perturbation of homeostasis on the core properties of the cell: transcription, translation, metabolism and control over protein activity. • To develop novel approaches to gauge the properties of individual cells and to model the behaviour of single cells, cell collectives in biofilms and multicellular structures. • To develop new chemical and biophysical tools for the analysis of cells and protein complexes in order to understand cellular sub-structure assembly. • To map the location and dynamics of supramolecular assemblies in the cytoplasm and cell membranes. • To manipulate the productivity of the cell and engineer new, tailored activities in the cell for industrial needs.'

Introduzione (Teaser)

Microbes are beneficial in areas such as pharmaceutical production and equally deleterious in food spoilage and disease. Understanding metabolic processes will aid in more efficient manipulation of microbes to increase output or restrict growth.

Descrizione progetto (Article)

Cellular metabolism takes place in a complex and dynamic environment in which enzymes perform under crowded conditions, low water activity and relatively constant regulated pH. The EU-funded NICHE (Network for integrated cellular homeostasis) project is investigating the molecular details of protein dynamics in Escherichia coli (E. coli) cells.

The researchers used super-resolution optical microscopy with photochemical switching and fast maturation as well as single-molecule tracking to probe the traffic of molecules. For tracking, fluorescent proteins with high photostability and high molecular brightness are needed.

Predictive modelling techniques are of paramount importance and NICHE is developing techniques to predict the effects of stress on transcription and translation of different gene groups. For this, the scientists are determining the cell-wide level of transfer RNA and its changes. The researchers have also developed novel optimisation-based techniques. These make possible a more efficient model building loop, from model inference to optimal experimental design and parameter estimation.

Analysis of regulatory interactions involving potassium may lead to disruption of pathogen potassium and pH homeostasis. NICHE researchers have applied their novel model development methods to potassium homeostasis in E.coli ligand binding. Creation of several mutants by the project will also help to boost understanding of ligand binding. Two papers in peer-reviewed journals have been published on this theme.

Currently, construction of a tumour growth model is underway. Future work will extend this model to a more typical phenotype of multiple tumour islands surrounded by stroma and supported with blood supply. Linked to this, a photometric method to measure tumour volume in animal systems has demonstrated the feasibility of a 3D infra-red time-of-flight camera.

NICHE methods and data stand to supply Pharma industries with meaningful data on bacterial cell dynamics that can be translated into the clinic via clinical efficacy trials. Data can also be used by the biotech industry to engineer new microbes for increased production.