Award details

19-BBSRC-NSF/BIO Characterizing efficiency and limitations of RNA regulators to achieve robust dynamic behaviours

Reference	BB/V00882X/1
Principal Investigator / Supervisor	Dr Francesca Ceroni
Co-Investigators / Co-Supervisors
Institution	Imperial College London
Department	Chemical Engineering
Funding type	Research
Value (£)	445,396
Status	Current
Type	Research Grant
Start date	04/01/2021
End date	19/05/2024
Duration	40 months

Abstract

Synthetic biology has made it possible to repurpose cells to operate as microscale factories, energy sources, and even computers. However, the introduction of pathways that are poorly tunable, and non-native to the host often causes undesired cross-interactions and unpredictable responses, and reliable engineering of cells remains a challenge. In particular, the expression of exogenous pathways triggers physiological changes in the host, usually leading to decreased growth due to consumption of cellular resources, a phenomenon known as cellular burden. These challenges could be mitigated using RNA-based regulators of gene expression, which are a programmable regulatory platform that imposes a lower burden on the host. Yet, little attention has been dedicated to systematically tuning the response function of RNA regulators. This project aims at screening and tuning the response function of two classes of RNA regulators. The regulators will then be employed as rapid, tunable components to better understand the burden response in E. coli. With improved knowledge of burden, we will engineer more robust bioproduction in E. coli. At every stage, experiments will be supported and guided by mathematical modelling.

Summary

Synthetic biology has made it possible to use cells to operate as microscale factories, energy sources, and even computers. However, the introduction of DNA circuits into cells can cause the cells to be stressed, something named as burden. Circuits that are poorly tunable, and non-native to the host often causes undesired cross-interactions and unpredictable responses, and reliable engineering of cells remains a challenge. In particular, the expression of exogenous pathways triggers physiological changes in the host, usually leading to decreased growth due to consumption of cellular resources, a phenomenon known as cellular burden. These challenges could be solved using RNA-based regulators of gene expression. These are systems which require transcription to occur but not translation, as no protein needs to be produced. The RNA acts as a regulatory molecule that can impact on the behaviour of the circuit in the cells. RNA circuits are programmable regulatory platform that imposes a lower burden on the host. Yet, little attention has been dedicated to systematically tuning the behaviour of RNA regulators. This project aims at screening and tuning two classes of RNA regulators. The regulators will then be employed as rapid, tunable components to better understand burden in bacteria. With improved knowledge of burden, we will modify bacteria to achieve better bioproduction of molecules of interest. Mathematical modelling will help our work by assisting the choice of experiments and circuits to be adopted.

Committee	Not funded via Committee
Research Topics	Microbiology, Synthetic Biology, Technology and Methods Development
Research Priority	X – Research Priority information not available
Research Initiative	UK BBSRC-US NSF/BIO (NSFBIO) [2014]
Funding Scheme	X – not Funded via a specific Funding Scheme

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