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Rusty cells: redox regulation of cell signalling and responses to stress

Primary Supervisor: Professor Corinne M. Spickett, Biosciences

Secondary supervisor: Dr Alex Cheong (Pharmacy) or Dr Alfred Fernandez-Castane (Engineering)

PhD project title: Rusty cells: redox regulation of cell signalling and responses to stress

University of Registration: Aston University

Project outline:

Redox balance is a central aspect of cellular function that regulates cell behaviour across many organisms from microbes to mammals. Cells maintain a balance between oxidizing species (such as hydrogen peroxide or superoxide) and antioxidants; changing the balance in either direction affects macromolecular interactions, gene expression, cell differentiation, proliferation or death. These responses are important in a wide variety of fields including antimicrobial resistance, responses to environmental toxins, cell manufacturing (BRIC) and ageing. While the general principles are well understood, many questions remain about the precise interactions that control specific processes. My group works on understanding the sensing and effects of redox imbalance at a molecular level in a variety of systems and applications. Three projects in this area are available.

  1. Regulation of mammalian protein-protein interactions by cellular redox state (Co-supervisor Dr Alex Cheong). Building on our previous research, we will use a broad, in vitro interactomics approach to determine the effect of oxidative and nitrosative stress on metabolic signalling proteins PTEN and pyruvate kinase and analyse their redox-dependent protein-protein interactions. The interactions will be validated in cellulo with functional tests to confirm their effects in cell differentiation and proliferation. The redox-dependent networks will be modelled for different cellular conditions with pathway mapping. The overall aim is to understand the effects of redox-dependent post-translational modifications on cell signalling processes that underlie ageing, inflammation and metabolism.

Approaches to Investigating the Protein Interactome of PTEN. Smith SL, Pitt AR, Spickett CM. J Proteome Res. 2021; 20(1):60-77.

Short-chain lipid peroxidation products form covalent adducts with pyruvate kinase and inhibit its activity in vitro and in breast cancer cells. Sousa BC, Ahmed T, Dann WL, Ashman J, Guy A, Durand T, Pitt AR, Spickett CM. Free Radic Biol Med. 2019 144:223-233.

  1. The role of redox balance in magnetotactic bacteria (Co-supervisor Dr Alfred Fernandez-Castane). Magnetotactic bacteria produce magnetosomes, structures that contain magnetite (Fe3O4) and allow the microbe to align in magnetic fields. Magnetosomes are of great interest as sources of magnetic nanoparticles for biotechnology applications, but knowledge of their synthesis, regulation and biochemical effects is still limited. Evidence is emerging that their production is redox-dependent, they may be redox-active in vivo and have protective effects against environmental stress. Building on expertise in growth of magnetotactic bacteria at Aston, this project will investigate the properties of the magnetosome membrane under different growth and redox conditions to determine how the bacteria avoid lethal oxidative damage from iron-dependent reactions and what antioxidant activities are present. Lipidomic and proteomic studies under different conditions will provide new understanding of magnetosome properties and enable improved magnetosome production.

Development of a simple intensified fermentation strategy for growth of Magnetospirillum gryphiswaldense MSR-1: physiological responses to changing environmental conditions. Alfred Fernández-Castané, Hong Li, Owen RT Thomas, Tim W Overton. New Biotechnol 2018; 46: 22-30

Analysis of SMALP co-extracted phospholipids shows distinct membrane environments for three classes of bacterial membrane protein. Teo ACK, Lee SC, Pollock NL, Stroud Z, Hall S, Thakker A, Pitt AR, Dafforn TR, Spickett CM, Roper DI.

Sci Rep. 2019; 9(1):1813.

Formation of Oxidatively Modified Lipids as the Basis for a Cellular Epilipidome. Spickett CM. Front Endocrinol 2020 Dec 21;11:602771.

BBSRC Strategic Research Priority: Renewable Resources and Clean Growth: Industrial Biotechnology & Understanding the Rules of Life: Immunology & Microbiology & Structural Biology & Systems Biology: Integrated Understanding of Health: Diet and Health

Techniques that will be undertaken during the project:

  • Mammalian cell culture (Project 1) or magnetotactic bacterial culture (Project 2). Both projects will use a combination of the biochemical, analytical and computational techniques below.
  • Biochemical techniques: cell culture, enzymatic assays, protein modification, enrichment and characterization, and molecular biology (mutagenesis and generation of fusion proteins).
  • Analytical techniques: liquid chromatography and mass spectrometry (LC-MSMS), PAGE and western blotting.
  • Computational techniques: quantitative data analysis, protein identification (proteomics), lipid and oxidized lipid identification (ox-lipidomics), pathway mapping.

Contact: Professor Corinne Spickett, Aston University