In light of the current Coronavirus pandemic, the deadline for applications has been extended to 24th May 2020. All interviews will now take place via Skype or other video conferencing platforms. The revised timeline is shown below.
Unfortunately, due to the closure of the university campus, we are currently unable to offer campus tours to sucessful candidates.
The call for the next cohort of MemTrain ESRs is now open. All applications must be submitted online at http://jobs.aston.ac.uk/
If you have any questions about the application process, please email the MemTrain team on firstname.lastname@example.org
If you wish to discuss any of the projects in more detail, please contact the relevant supervisor, or Dr Alan Goddard email@example.com
1. Development of therapeutics for dermal and ocular use based on plant bioactive compounds
The advancement of phytochemical interest and activity and a rising demand for plant bioactive compounds have led to elucidation of the chemical composition and biological properties of a number of plant species. Most of the bioactive compounds, including plant phenolics, tannins, terpenoids and proteins, are not readily able to cross the lipid barrier of the dermal surface. In consequence bioavailability and efficacy are relatively poor. The use of delivery complexes seems to cause least side effect in terms of tissue damage. Of this family it is notable that improved drug absorption through the dermal layer is associated with lipid-based nanovesicles, such as liposomes, and ethosomes. Practical use of those vesicles is still limited, however, because of (e.g.) the lack of long-term stability and specific encapsulation requirements. There is, therefore, significant potential value in the design of synthetic polymers that can combine extraction and encapsulation ability whilst maintaining functionality of active compounds in the form of nanostructures. Such systems are equally applicable to the ocular environment.
The key to the success of this project will depend upon the design and development of an optimised hyper-associating styrene-maleic acid copolymer, or analogous structure, based on the expertise developed through existing collaborations between LHS (Rothnie, Goddard, Bill) and EAS (Tighe, Topham). A range of appropriate plant-based natural resources are available. The project will develop both synthetic and analytical skills.
The project will be supported by i+Med, a medical device research company specialising in controlled release and its biomedical applications
Industrial: Dr Virginia Saez: firstname.lastname@example.org
2. Understanding age and diabetes-related changes in erythrocyte membranes.
There is evidence that both ageing and diabetes alter the fluidity of the red blood cell membrane leading to dysfunction, but the molecular basis for this is not well understood. Diabetes is a metabolic disorder closely linked to cardiovascular disease risk and inflammation, and is known to lead to the modification of proteins by the formation of advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), an example of which is the widely used HbAa1c diagnostic biomarker for chronic diabetes. Ageing has also been shown to result in an increase in lipid and protein oxidation.
This project will investigate the correlation between membrane fluidity, (phospho)-lipid composition and the formation of AGEs and ALEs on erythrocyte membrane proteins, using erythrocytes that have been treated diabetes-related stress conditions or from aged volunteers. The methods with include fluorescent-based assays for membrane permeabilization and fluidity, western blotting for the formation of AGEs and ALEs, and mass spectrometry to monitor phospholipid changes. The pro-inflammatory effects of these model diabetic erythocytes will also be investigated. This will lead to an understanding of how diabetes and ageing lead to cellular dysfunction, and may provide insights that will lead to better management and treatment of disease and healthier ageing.
The project will be supported by our industrial partner SCIEX, who bring expertise in the analysis of biomolecules, especially using mass spectrometry.
Associate Supervisor: Dr James Brown, Aston University: email@example.com
Industrial: Stephen Ayris, SCIEX: firstname.lastname@example.org
3. The role of protein lipoxidation in cell membrane signalling.
During inflammation and metabolic imbalance, reactive oxygen species are formed, which leads to oxidative stress, resulting in oxidative damage to phospholipids in cell membranes, producing a variety of short- and long-chain lipid oxidation products. The reaction of these oxidized lipid products with proteins (lipoxidation) can change the structure, activity and cellular effects of the protein. The formation of lipoxidation products has been demonstrated in a variety of metabolic, structural and signalling proteins across a range of cellular models relating to cardiovascular disease and cancer. Although the result is often loss of function, in some cases detrimental gain of function is observed, which may be related to a number of changes in the protein, particularly changes in cellular localization of the protein including targeting to membrane compartments.
This project will investigate the effect of lipoxidation of the membrane-associated signalling proteins HRas, a small G-protein involved in MAPK signalling, and phosphatase and tensin homolog (PTEN), a regulator of the Akt pathway, both of which are central to key intracellular signalling pathways that are aberrantly activated in diseases such as cancer. Proteins will be treated with reactive lipid oxidation products in vitro and the protein isoforms will be characterized by novel chromatography approaches and ion mobility mass spectrometry. Cultured cell lines expressing wild type and mutant proteins will be treated with reactive lipid oxidation products and the effects on protein subcellular localization and activity will be monitored by fluorescence microscopy and western blotting respectively. This will lead to the identification of new mechanisms for disease development and progression and will enhance our understanding of the role of lipoxidation in disease.
The project will be supported by our industrial partners Waters, wolrld leaders in ion mobility mass spectrometry and ThermoFisher for the development and application of advanced chromatography.
4. The effect of lipid oxidation on membrane protein activity.
During inflammation and metabolic imbalance that occur in diseases including cancer, cardiovascular disease and diabetes, reactive oxygen species are formed leading to oxidative stress. This results in oxidative damage to phospholipids in cell membranes, producing a variety of reactive lipid oxidation products, which form covalent adducts with proteins, altering their structure and activity and affecting their cellular function. However, we are only now starting to identify in sufficient detail the changes that occur to the proteins to link this to the effects, enabled by access to the latest technologies.
This project will use model liposome and cell systems to investigate how the G-protein coupled adenosine receptor A2aR, is affected by oxidative changes in the surrounding membrane phospholipid environment. A2aR is present at high levels in basal ganglia, the vasculature and T-lymphocytes, has been shown to have a range of roles in the health of the heart and vasculature and in inflammation, and its activity has been linked to disease such as neurodegeneration and cancer. Changes in activity of the protein will be measured using binding assays, and mass spectrometry will be used to analyse phospholipid oxidation and covalent adducts with the protein. Styrene-maleic acid lipid particle technology (SMALPs, also known as nanodiscs) will be used to investigate the noncovalent interactions of oxidized and non-oxidized lipids with the protein, and the ability of A2aR in different lipid environments to be stimulated by agonists and downstream signalling will be measured and correlated with the membrane changes. This will answer fundamental questions on the role of protein-associated lipids and lipid oxidation products in the activity of a key class of membrane protein.
The project will be supported by the mass spectrometry team of our industrial partner Waters, a world-leading mass spectrometry and separations company.
5. De Novo design of membrane protein channels using a multidisciplinary approach
Synthetic Biology has an enormous array of potential applications, ranging from the production of green biofuels to the use of programmable cells to treat cancer. One aspect of Synthetic Biology is the de novo design of protein sequences that result in novel biological building blocks with innovative functions. A significant bottleneck in the development of de novo design is an understanding of the rules that govern how proteins fold. Traditionally, biophysical methods such as FRET, CD and NMR are used to understand the folding of membrane proteins. However, computational methods are becoming key, not only in the analysis of data but also generating meaningful predictions of the structure of proteins intractable by other methods. Multidisciplinary approaches that combine computational prediction, as well as lab-based experiments, provide a deep insight into the structure of membrane proteins which can, in turn, be used to design novel sequences.
This is a challenging project and will address both the de novo design of novel sequences as well as the re-design of naturally occurring scaffolds to form membrane protein channels. This builds upon recent work in our lab which has successfully designed and expressed stable helical bundles which autonomously fold and insert into a membrane environment. This multidisciplinary project will combine laboratory-based experiments (Molecular Biology, Protein Expression, Biophysics) with Computational Biology (Molecular Modelling and Membrane Protein Simulations) to generate a series of sequences which autonomously fold to act as ion channels. Furthermore, the experimental data discovered during the project will be used to further develop a novel, cutting edge computational structure prediction method with our industrial partner Syndial. Overall, this is a challenging, multidisciplinary project that will explore the exciting area of de novo protein design. In the process of this PhD, students will gain insight and technical expertise in both experimental-based lab work as well as computational approaches.
Industrial: Professor David Lowe: email@example.com
6. Identification of new inhibitors of aquaporin water channel function
Our consortium has access to the laboratory facilities, knowledge, data, technologies and networks needed to be able to progress a programme of medicines research and development.
With advisory input from our national and international partners, the student will work on the development of new drugs that target the function of aquaporin water channels (AQP). AQPs control the flow of water in all forms of life; in humans their dysfunction is associated with diverse diseases. The project will include the expression of AQPs in mammalian cells, their biochemical and biophysical assessment and compound screening. New aquaporin inhibitors will be benchmarked against existing molecules in novel functional assays.
The student will gain a broad overview of the drug discovery process. Furthermore, the student will gain specific skills such as tissue culture, protein biochemistry, high-throughput screening and biophysical characterization. Finally, the student will gain a unique perspective on a career in a not-for-profit, independent technology and innovation centre, including risk management and business development skills.
Academic: Professor Roslyn Bill, Aston University: firstname.lastname@example.org
7. Strain optimisation for production of high value chemicals.
The global economy has an unsustainable dependence on fossil raw material and concerns about environmental sustainability are becoming more acute. Biotechnological processes using microorganisms as cell factories to produce valuable compounds from renewable biomass are an attractive alternative, and an increasing number of platform and high-value chemicals are being produced at industrial scale using this strategy. However, many microbial processes are not implemented at industrial level because the product yield is poorer and more expensive than achieved by chemical synthesis. It is well-established that microbes show stress responses during bioprocessing and one reason for poor product output from cell factories is production conditions that are ultimately toxic to the cells, often at the level of the cell membrane. Examples of stresses that are demonstrably membrane-centric are solvents, e.g. butanol production by Clostridia and ethanol production by yeast, and weak acids such a lactic acid produced by bacteria. This project will seek to alter the cell membrane of industrial microbes to increase tolerance to stresses during bioprocessing.
Biocleave have patented technology (CLEAVE™) for genome editing of Clostridial species. Clostridia have significant potential within bioproduction of both native compounds e.g. butanol, and to be engineered to make additional molecules. However, Clostridia have traditionally been difficult to manipulate on a genetic level. The introduction of CLEAVE technology, based on endogenous CRISPR, has the potential to be a game changer and provides an opportunity to greatly increase the utility of Clostridia in this field. This project will use a powerful combination of in vitro assays, microbial cell culture, and ‘omics technologies to identify the molecular targets suitable for overcoming stresses in bioprocessing e.g. lipids and transporters. Following this, CLEAVE will be used to create new strains, followed by strain characterisation to determine if the desired membrane alterations have been achieved and if tolerance to a particular stress (or stresses) has been increased. Iterative design-build cycles will be undertaken as appropriate to further improve the strains.
Academic: Dr Alan Goddard, Aston University: email@example.com
Industrial: Dr Liz Jenkinson: firstname.lastname@example.org