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BiPAS CDT projects  [PDF 549KB] 

For comprehensive information including project aims and a full description, please download the above PDF.

Overview of projects

The (un)structural biology of protein-RNA recognition unravelled by high-resolution HDX-MS guided modelling

Project ID: 2020_001
1st supervisor: Antoni Borysik (Department of Chemistry)
2nd supervisor: Maria (Sasi) Conte (Randall Centre for Cell & Molecular Biophysics)
Project type: Computational/experimental

Project overview

In this project the student will apply new high-resolution modelling techniques based on hydrogen deuterium exchange mass spectrometry (HDX-MS) to understand protein-RNA recognition. Borysik is developing a range of novel web-based tools for HDX-MS including HDXmodeller which permits the characterisation of protein solvent exchange in full resolution. We expect these tools to be very powerful particularly for proteins that are challenging for conventional methods such as those that contain significant disorder. This studentship is a great opportunity for the right candidate to pioneer the application of these methods on an important protein system that has thwarted characterisation by classical techniques.

Structural insights in the design of protein-based biomaterials

Project ID: 2020_002
1st supervisor: Alex Brogan (Department of Chemistry)
2nd supervisor: Sherif Elsharkawy (Department of Oral, Clinical & Translational Sciences)
Project type: Experimental

Project overview

Protein-based biomaterials are increasingly sought after for a multitude of applications ranging from industrial biocatalysis to tissue engineering. Protein-based materials have significant advantages over synthetic materials such as improved biocompatibility (for tissue engineering) and energy efficiency (for biocatalysis). Furthermore, incorporating proteins into materials can bring additional function and capacity such as improved robustness and enhanced activity. Key to the success of protein-based biomaterials is maintaining and controlling the structure of the biomolecule. This project will explore the optimization of protein-based biomaterials for a variety of applications through a systematic and comprehensive biophysical study of protein structure, stability, and function.

Mechanoregulation of cell-matrix interactions in human intestinal organoid-based models of inflammatory bowel disease

Project ID: 2020_003
1st supervisor: Eileen Gentleman (Centre for Craniofacial and Regenerative Biology)
2nd supervisor: Joana Neves (Centre for Host-Microbiome Interactions)
Project type: Experimental

Project overview

Inflammatory bowel disease (IBD) can impact the matrix surrounding the gut epithelium, causing fibrosis and fistulae; however, it is unknown whether mechanical changes to the intestinal wall are a cause or consequence of inflammation. This project will establish human intestinal organoid (HIO)-based models of IBD which will allow us to use a combination of microrheology and microindentation to monitor how HIO modulate their local mechanical properties. This interdisciplinary approach will allow us to unravel how cell-mediated mechanical changes to the mesenchyme contribute to IBD-like phenotypes in the epithelium. Through this, we aim to reveal novel matrix-modulating targets that can be exploited therapeutically to treat IBD.

Biosynthesis of 2D nanomaterials in bacteria

Project ID: 2020_004
1st supervisor: Mark Green (Department of Physics)
2nd supervisor: Roland Fleck (Centre for Ultrastructural Imaging)
Project type: Experimental

Project overview

Nanomaterial have found use in biological imaging and therapy, although they remain relatively hard to prepare in large amounts. Here, we will explore the synthesis of advanced materials, useful in cancer therapy and energy applications, using bacteria as the reaction medium, providing a cheap and efficient route utilizing biological processes rather than expensive high temperature chemical routes. Electron microscopy provides unrivaled 3D resolution for in situ characterization of nanoparticle synthesis at near atomic resolution. The project will provide new insight into nanoparticle synthesis together with innovation in the application of electron microscopy for soft materials research.

Developing multiscale models to study molecular transport into tissues

Project ID: 2020_005
1st supervisor: Chris Lorenz (Department of Physics)
2nd supervisor: Martin Ulmschneider (Department of Chemistry)
Project type: Computational

Project overview

The goal of this project is to develop realistic 3D tissue models to allow simulation of molecular transport across scales. Tissues rely on the supply of a wide range of nutrients and metabolites from circulation to carry out their biological functions. To arrive at their final cellular destinations these molecules need to cross a variety of physiological barriers. At present, this process is poorly understood, chiefly due to the absence of multiscale in silico models that allow capturing perfusion, extravasation, and diffusive flux in tissues in its entirety. In this project centimetre-scale organs will be constructed by integrating atomic detail models of physiological barriers into micrometer-scale models of the vasculature and tissue fine-structure.

Mapping the conformational landscape of intrinsically dynamic proteins across broad time scales

Project ID: 2020_006
1st supervisor: Argyris Politis (Department of Chemistry)
2nd supervisor: Manuel Mueller (Department of Chemistry)
Project type: Experimental/Computational

Project overview

This studentship aims to dissect the conformational dynamics underpinning function in intrinsically dynamic proteins. To do so, we will employ a unique combination of hydrogen deuterium exchange mass spectrometry (HDX-MS)—carried out in timescales spanning five orders of magnitude—with biochemical tools and advanced modelling. To showcase our method, we will use the challenging p53 protein comprising both folded and intrinsically disordered regions. The gain in mechanistic understanding will enable a step-change in monitoring the dynamics of such a complex nanomachine and provide a template to understand—at molecular level—other difficult to tackle biological systems.

Multi-scale investigation of the conformations of musk odorants and their binding to human musk receptors

Project ID: 2020_007
1st supervisor: Maria Sanz (Department of Chemistry)
2nd supervisor: Franca Fraternali (Randall Centre for Cell & Molecular Biophysics)
Project type: Experimental/Computational

Project overview

Musk odorants are key compounds in perfumery due to their distinctive animal and sensual notes. However, insight on the determinants of musk smell has been hampered by the lack of structural information on receptors and on the musks themselves. This project will determine the structural elements associated to musk smell by characterising musk conformations and their interactions with human musk receptors through the combination of multiscale experimental and computational studies. Our results will provide crucial data for understanding musk identification and, more broadly, their pharmacological effects. Our data will unlock opportunities for rational design and development of new musks.

Mechanoregulation of cytotoxic T cell target cell killing

Project ID: 2020_008
1st supervisor: Katelyn Spillane (Department of Physics)
2nd supervisor: Robert Köchl (Department of Immunobiology)
Project type: Experimental

Project overview

Cytotoxic T cells form immune synapses with infected or transformed cells to instruct those cells to die. The process is selective, sensitive, and rapid and is initiated by piconewton-scale forces transmitted to receptor-antigen bonds. Whether mechanical noise from the environment dysregulates these interactions, or whether the immune synapse can insulate against large external forces, is not known. Here we will investigate how mechanical forces from the environment influence the mechanical and chemical signals in the immune synapse that enable cytotoxic T cells to recognise and destroy their targets.

Time-correlated single photon-based lightsheet fluorescence lifetime imaging microscopy

Project ID: 2020_009
1st supervisor: Klaus Suhling (Department of Physics)
2nd supervisor: Maddy Parsons (Randall Centre for Cell & Molecular Biophysics)
Project type: Experimental

Project overview

In lightsheet microscopy, a thin slice of the sample is illuminated, and the image is observed at right angles with a camera. Fluorescence lifetime imaging (FLIM) can image complex dynamic processes, and to help us to understand life and disease on a molecular scale. FLIM is best done by assembling the image from individual photons - the most accurate and sensitive way of doing this. Conventional cameras can capture images well, but they cannot photon count in the way needed for lightsheet FLIM. The project will use a single-photon sensitive FLIM lightsheet microscope with a special photon counting camera. This unique instrument will be used to make movies of fluorescence under low light conditions in live cells in complex 3D environments to study diffusion of small fluorophores.

New tools for neurobiology: linking neurons and artificial cells

Project ID: 2020_010
1st supervisor: Mark Wallace (Department of Chemistry)
2nd supervisor: Juan Burrone (Centre for Developmental Neurobiology)
Project type: Experimental

Project overview

Brain-computer interfaces typically rely on invasive electrodes. A major flaw in these approaches is the mismatch between the practical number of electrodes, and the number of neurons. Recent advances in bottom-up synthetic biology suggest that artificial cells might provide an alternative route to create soft, biocompatible, brain interfaces that would circumvent current limitations. Here we will design basic interconnects between artificial cells and neuronal cells to create proof-of-principle sensors and actuators of neuronal function. This toolset will provide new routes to help understand the nanoscopic functional organization of neuronal networks.

Integrated confocal Raman-fluorescence microscopy for intracellular protein and lipid imaging in neural stem cell cultures

Project ID: 2020_011
1st supervisor: Mads Bergholt (Centre for Craniofacial and Regenerative Biology)
2nd supervisor: Andrea Serio (Centre for Craniofacial and Regenerative Biology)
Project type: Experimental

Project overview

Lipids of the nervous system have major consequences for brain structure, function, behaviour and diseases. State-of-the-art fluorescence microscopy is specific for proteins but offers no insights into lipids. The goal of this PhD project is to drive forward a new paradigm of microscopy that enables fully correlative lipid and protein imaging. We will introduce a ground-breaking new confocal fluorescence microscope through novel integration with confocal Raman spectroscopy. We will develop a pipeline for correlative protein and lipid imaging from the cellular to tissue scale. We will finally apply the technique to characterise lipid composition, lipid rafts dynamics and time-dependent changes in elongating spinal cord axons and cortical axons.

Exploring the mechanisms of action of dietary polyphenols in the vascular system across scales

Project ID: 2020_012
1st supervisor: Carla Molteni (Department of Physics)
2nd supervisor: Ana Rodriguez-Mateos (Division of Diabetes and Nutritional Sciences)
Project type: Computational/Experimental

Project Overview

Cardiovascular disease is less common in premenopausal women, suggesting vascular benefits of estrogen. Clinical studies have highlighted that a diet rich in polyphenols present in berries can improve vascular function in women. The structure of such polyphenols has similarities to estrogen and they may therefore interact with estrogen receptors. We will explore whether and how selected phenolic metabolites, in which the ingested polyphenols are transformed after consumption, interact with estrogen receptors through innovative computer simulation methods to elucidate their potential mechanisms of action at the molecular level. This will complement in vitro and in vivo studies to elucidate how the molecular details translate across the cellular and macroscopic scales.

The impact of topography-induced local cytoskeletal rearrangement on metabolic cell requirements

Project ID: 2020_013
1st supervisor: Ciro Chiappini (Centre for Craniofacial and Regenerative Biology)
2nd supervisor: Andrea Serio (Centre for Craniofacial and Regenerative Biology)
Project type: Experimental

Project Overview

Topographical cues are widely investigated as microenvironmental stimuli for stem cells differentiation in regenerative medicine. In particular, we have recently shown that high aspect ratio nanomaterials (nanoneedles) stimulate directly multiple elements of the cell, inducing local rearrangements of endocytic vesicles, cytoskeleton, and nuclear envelope. Yet, to date there is no systematic study focusing on how these dramatic rearrangements impact the organelle shuttling and distribution across cell compartments or how organelle dynamics are carried through these strongly altered networks. In this project we will focus on the effect of cytoskeletal local pinning, wrapping and sharp bending around nanoneedles on shuttling dynamics, biogenesis and function of mitochondria in neural progenitors, neurons and astrocytes.

Creating dynamic functional membrane structures; the molecular basis of biomembranes

Project ID: 2020_014
1st supervisor: Paula Booth (Department of Chemistry)
2nd supervisor: Snezhana Oliferenko (Randall Centre for Cell & Molecular Biophysics)
Project type: Experimental

Project Overview

Biological systems organise themselves with efficiency and precision. We are far from a complete understanding of this natural self-assembly, which in turn limits our ability to mimic biological construction in tuneable synthetic systems. Natural membranes are formed from only two core components, proteins and lipids, but they conceal a functional sophistication that cannot be mimicked in artificial systems. We want to understand how this collective emergent behavior of membranes arises and exploit this in artificial cells. These goals will be achieved by integrating biophysics, chemistry and synthetic biology approaches on individual molecules through supramolecular chemistry to complex biological systems.