Research projects

All self-funded projects can be applied to throughout the year. Please note that not all projects are available in the IPhD route. 

+++

Regulation of AMP-activated protein kinase by steroids

Supervisor: Ian Salt

Project background: AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade activated by low energy levels [1]. AMPK phosphorylates targets leading to suppression of ATP-consuming pathways and stimulation of ATP producing pathways, such that the AMP:ATP ratio returns to normal [1]. Reduced levels of nutrients can therefore activate AMPK if they cause ATP levels to fall. Similarly, overnutrition may suppress AMPK activity. As a consequence, activation of AMPK has been proposed as a potential therapy for metabolic disorders including obesity and type 2 diabetes. Recent studies have indicated that the steroid glucocorticoid hormones, that regulate metabolism and are anti-inflammatory, can activate AMPK in macrophages [2]. Furthermore, the glucocorticoid dexamethasone has been reported to activate AMPK in muscle, liver and hypothalamus [3,4], yet inhibit AMPK in adipocytes [3]. AMPK also has anti-inflammatory actions [5].

This project will examine whether glucocorticoids and other steroid hormones regulate AMPK and whether AMPK conversely influences steroid signalling. Furthermore, the functional consequences of any such regulation will be investigated.

Techniques: The project will provide excellent training in a range of techniques associated with molecular biology, cell biology and biochemistry. These include but are not limited to mammalian cell culture, gel electrophoresis and immunoblotting, fluorescence microscopy, nutrient flux and signalling assays.

References

1. Salt IP, Hardie DG (2017) AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway With Key Roles in the Cardiovascular System. Circ Res. 120:1825-41.
2. Caratti et al (2023) Macrophagic AMPKα1 orchestrates regenerative inflammation induced by glucocorticoids. EMBO Rep. 24;e55363
3. Christ-Crain et al (2008) AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing’s syndrome. FASEB J. 22;1672–83
4. Liu et al (2016) Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling. Mol Pharmaceutics 13;73-84
5. Mancini et al (2017) Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation. Mol Cell Endocrinol 440:44-56.

---

Integrated PhD (October-April)

Our Integrated PhD combines an MSc and PhD project in a 1+3+1 format. There are two options when choosing to apply for the IPhD and these are shown below. Please review how to apply section for more information. 

Option A: Choose from the listed projects.

You can select from the listed projects below and choose your MSc from the options listed on that project. 

+++

Exploring the roles of methionine sulfoxide reductases in mammalian cells (available as IPhD)

Supervisor: Brian Smith

MSc choices: Chemical Biology, Biotechnology, Biomedical Sciences

Project description: Methionine oxidation is an enigmatic, stereo specific posttranslational modification of proteins that is traditionally thought to be a result of oxidative damage. Cells express enzymes that act as methionine sulfoxide reductases (Msr) with two distinct families, MsrAs and MsrBs acting on the S and R epimers, respectively. Intriguingly, the mammalian endoplasmic reticulum, an oxidising compartment of the cell, is only known to contain one Msr, MsrB3, leaving open the question as to whether methione-S-sulfoxide can be repaired in this location and indeed whether MsrB3 acts as a reductase or an oxidase. Defects in MsrB3 expression or function are linked to health conditions including deafness indicating that it is worthy of further study. In this project, you will explore MsrB3 function at the structural and cellular level exploiting new chemical biological tools in collaboration with Prof Hartley (School of Chemistry).

Techniques used:

• Biomolecular NMR spectroscopy,
• Protein X-ray crystallography,
• Biochemical assays,
• Chemical biology tool compounds,
• Cell biology

References:

1. Cao Z, Mitchell L, Hsia O, Scarpa M, Caldwell ST, Alfred AD, Gennaris A, Collet JF, Hartley RC, Bulleid NJ. Methionine sulfoxide reductase B3 requires resolving cysteine residues for full activity and can act as a stereospecific methionine oxidase. Biochem J. 2018 Feb 28;475(4):827-838. doi: 10.1042/BCJ20170929.

---

+++

Structural systems biology of Staufen1:RNA transactions (available as IPhD)

Supervisor: Laura Spagnolo 

MSc choices: Chemical Biology [MSc], Stem Cell Engineering for Regenerative Medicine [MSc], Biotechnology [MSc], Biomedical Sciences [MSc]

Outline: Since its discovery, Staufen1 has been studied for its involvement in a diverse set of aspects of RNA metabolism, ranging from RNA localisation to decay. Given its pivotal role in cellular RNA metabolism, several studies have explored the mechanistic impact of Staufen1 in a wide variety of cell functions ranging from cell growth to cell death, as well as in various disease states. This PhD project aims to identify the molecular mechanism governing the functions of Staufen1 protein, using our unique expertise in the structural and quantitative biology of protein:nucleic acid complexes, track record on Staufen1 structural biochemistry, and access to beyond-state-of-the-art technology.

To gain quantitative molecular knowledge on the formation of Staufen1:RNA complexes, this project will focus on the detailed individual analysis of Staufen1:RNA complexes in vitro; as well as on gathering detailed information of such assemblies combining light and electron microscopy approaches.

Techniques

• Gene cloning, Protein over-expression purification, biochemical and cellular assays
• Reconstitution of multi-protein and protein:RNA complexes
• Assay development
• Cryo-electron Microscopy
• SAXS
• FRET; FRET-FLIM
• Super-resolution microscopy

---

+++

The molecular basis of cell self-renewal and pluripotency in embryonic stem cells (available as IPhD)

Supervisor: Laura Spagnolo 

MSc choices: Chemical Biology [MSc], Stem Cell Engineering for Regenerative Medicine [MSc], Biotechnology [MSc], Biomedical Sciences [MSc]

Outline: Self-renewal and pluripotency are the main characteristics of embryonic stem cells (ESCs). Nanog is the key transcription factor that controls both self-renewal and pluripotency of ESCs.

The aims of this project are to understand on a biochemical and molecular level how Nanog self-assembles and binds to DNA. This project will involve expressing and purifying Nanog-containing macromolecular complexes, developing protocols for studying their three dimensional structure, and designing biophysical characterisation experiments (in both single molecule and ensemble setups) to unravel the molecular determinants of Nanog functions.

Techniques

• Gene cloning, Protein over-expression purification, biochemical and cellular assays
• Reconstitution of multi-protein and protein:DNA complexes
• Assay development
• Cryo-electron Microscopy
• SAXS
• FRET; FRET-FLIM
• Super-resolution microscopy

---

+++

Ubiquitin signals in Parkinson’s disease (available as IPhD)

Supervisor: Helen Walden  

MSc choices: TBC

Outline: Ubiquitin signalling controls almost every cellular process in humans, including targeting poorly folded proteins for destruction to prevent them harming the cell. When ubiquitin signalling goes wrong, many different disease states can occur, including neurodegenerative disorders such as Parkinsons Disease (PD).

One gene associated with PD is parkin, which gives rise to an enzyme responsible for tagging many different proteins with ubiquitin. The aims of this project are to understand on a biochemical and molecular level how parkin targets a specific substrate, Miro1, and how the ubiquitin signals applied to Miro1 are edited & interpreted.

This project will involve expressing and purifying multiprotein complexes, and developing protocols for generating the ubiquitin signals, and enzymatic assays for the regulation of these signals.

Techniques

• Cloning and sequencing
• Protein expression purification, and biochemistry
• Assay development
• X-ray crystallography
• Cryo Electron Microscopy
• Analysis of high resolution structures

References

1. Gundogdu M, Tadayon R, Salzano G, Shaw GS, Walden H. A mechanistic review of parkin activation. Biochim Biophys Acta Gen Subj. 2021 Jun;1865(6):129894. doi: 10.1016/j.bbagen.2021.129894.20.PMID: 33753174
2. Kumar A, Chaugule VK, Condos TEC, Barber KR, Johnson C, Toth R, Sundaramoorthy R, Knebel A, Shaw GS, Walden H. Parkin-phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity. Nat Struct Mol Biol. 2017 May;24(5):475-483. doi: 10.1038/nsmb.3400. Epub 2017 Apr 17.PMID: 28414322

---

+++

Understanding the effects of potassium ions on biomolecular & cellular structure & function (available as IPhD)

Supervisor: Brian Smith

MSc choices: Chemical Biology, Biotechnology, Biomedical Sciences

Project description: Potassium is the most abundant intracellular monovalent cation, but its effects on biomolecular structure and function are only known for a limited number of cases. Techniques that can observe the direct interaction between potassium ions and biomacromolecules have so far been limited to studying high affinity binding sites. In this project you will develop novel NMR based methods to observe low affinity interactions directly and relate them to structural and functional outcomes. In parallel, you will develop new sensors for intracellular potassium concentration leveraging AI based protein design algorithms.

Techniques used are Biomolecular NMR spectroscopy and Artificial Intelligence based protein design.

References:

1. Torres Cabán, C. C., Yang, M., Lai, C., Yang, L., Subach, F. V., Smith, B. O. , Piatkevich, K. D. and Boyden, E. S. (2022) Tuning the sensitivity of genetically encoded fluorescent potassium indicators through structure-guided and genome mining strategies. ACS Sensors, 7(5), pp. 1336-1346. (doi: 10.1021/acssensors.1c02201)

---

Option B: Create your own research proposal

You can create your own project, source a supervisor and they will choose an MSc programme that aligns with your research proposal. 

+++

Create your own PhD proposal

1. Create your own proposal - approximately 1000 words and must include:
   • a straightforward, descriptive, and informative title
   • the question that your research will address
   • an account of why this question is important and worth investigating
   • an assessment of how your own research will engage with recent research in the field
   • a brief account of the methodology and approach you will take.
2. You will need to contact a supervisor prior to application, using the search function.

Supervisor Search

Based on your proposal, your supervisor will choose an MSc programme that aligns with your research interests. 

---

Overview

Our biochemists and molecular biologists study the “molecules of life”, the essential molecular components of all living organisms. We aim to understand how these molecules perform their functions, using a variety of modern molecular and biochemical approaches including structural analysis at the atomic level by X-ray crystallography, NMR spectrometry, and other biophysical methods. The knowledge gained by this research gives us opportunity to invent and develop novel ways of altering biological processes to our advantage, with applications in molecular medicine, biotechnology, synthetic biology, as well as industry.

PhD programmes in biochemistry and biotechnology will carry out a cutting-edge research project in an area that aligns with the expertise of one or more of our principal investigators in the fields of biochemistry and biotechnology. The subject of the project may be fundamental “blue skies” science or may be targeted at an important application. Projects may also be related to basic science and integrate with our existing research themes, while other projects are more focused on translational aspects of our research.

Some of our current research areas are:

• cell signalling mechanisms in mammals, plants and insects
• mitochondrial biogenesis and mitochondrial proteins
• mechanisms of DNA sequence rearrangements
• DNA sequences in human disease
• genetic circuits and switches for synthetic biology
• plant molecular biology
• photosynthesis, plant photobiology, circadian factors in plants
• structural determination by NMR and X-ray crystallography
• structural bioinformatics, molecular modelling
• drug receptors, molecular pharmacology
• nuclear genomic architecture
• mechanisms of intracellular trafficking
• protein folding, targeting and modification
• protein-protein and protein-DNA interactions
• cell-surface interactions

Our PhD programme provides excellent training in cutting edge technologies that will be applicable to career prospects in both academia and industry. Many of our graduates become postdoctoral research associates while others go on to take up positions within industry, either locally or overseas. We have strong academic connections with many international collaborators in universities and research institutes.

Funds are available through the College of Medical, Veterinary and Life Sciences to allow visits to international laboratories where part of your project can be carried out. This provides an excellent opportunity for networking and increasing your scientific knowledge and skill set.

Study options

PhD

• Duration: 3/4 years full-time; 5 years part-time

Individual research projects are tailored around the expertise of principal investigators.

Integrated PhD programmes (5 years)

Our Integrated PhD allows you to combine masters level teaching with your chosen research direction in a 1+3+1 format. 

International students with MSc and PhD scholarships/funding do not have to apply for 2 visas or exit and re-enter the country between programmes. International and UK/EU students may apply.

Year 1

Taught masters level modules are taken alongside students on our masters programmes. Our research-led teaching supports you to fine tune your research ideas and discuss these with potential PhD supervisors. You will gain a valuable introduction to academic topics, research methods, laboratory skills and the critical evaluation of research data. Your grades must meet our requirements in order to gain entry on to your pre-selected PhD research project. If not, you will have the options to pay outstanding MSc fees and complete with masters degree only.

Years 2, 3 and 4

PhD programme with research/lab work, completing an examinable piece of independent research in year 4.

Year 5

Thesis write up.

MSc (Research)

• Duration: 1 year full-time; 2 years part-time