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Mrc Impact PhD Training Partnership at The University of Nottingham

The University of Nottingham is pleased to invite applicants to apply for a new opening PhD position in veterinary medicine. The initial contract for this position is 5 years. The deadline for applying is January 17, 2020.

Applications are now open for a range of exciting projects to study Complex Disease for a September 2020 start.

Interviews will take place the week commencing 17 February 2020.

Application details are on the MRC IMPACT DTP website.

The studentships will commence in October 2020, and a stipend (15,009 for 2019/20) and fee waiver for 3.5 years is available for UK applicants, plus research training support grant, travel and laptop allowance

Fully funded studentships are available for UK applicants. EU applicants who are able to confirm that they have been resident in the UK for at least three years before October 2020 may also be eligible for a full award. EU students who are not able to prove that they meet the residency criteria may apply for a fees only award.

IMPACT is a DTP funded by the MRC between three academic partners - the Universities of Birmingham, Nottingham and Leicester. Research projects within the DTP are focused around the theme of Complex Disease, which allows doctoral students to benefit from a diverse range of projects and skills within the cohort, stimulating students to think 'outside the box' and perform innovative, world-leading research. The DTP also provides the opportunity for students to benefit from the expertise of our research partner, the Research Complex at Harwell.

A cross-resolution preclinical imaging framework based on MRI and light sheet microscopy to assess post-stroke axonal regrowth

PI: Dr Matteo Bastiani, School of Medicine, University of Nottingham, Associate Professor Rebecca Trueman University of Nottingham and Professor Steve Watson University of Birmingham/COMPARE

Summary: Magnetic Resonance Imaging (MRI) is an important diagnostic and research tool that provides detailed images of the brain non-invasively. However, it is limited by resolution (approx. 1mm). The development of models that can link features of the image to underlying cellular information at the micrometre scale would significantly improve specificity and sensitivity of diagnosis and help to tailor treatments to individual patients. We aim to develop such a model by directly comparing MRI to three-dimensional microscopy. Then, we will test the framework on a stroke animal model. Stroke is the second cause of death worldwide and produces a complex pattern of brain injury followed by various degrees of cellular regrowth. It is therefore an optimal clinical case to validate our model, leading to the development of accurate and precise imaging-based biomarkers.

The student will engage in specialist training with ex vivo and in vivo (subject to the experience and wishes of the applicant) animal handling, preclinical imaging, and data analysis techniques. The successful candidate will also acquire new computational and modelling skills as well as learn practical laboratory procedures to make a brain transparent. This will allow the student to model features of the MR images using 3D microscopy images.

Determining structure of the Pre-Initiation RNA-protein Complex formed during canonical translation initiation of HIV mRNA

PI: Dr Aditi Borkar, School of Veterinary Medicine and Science, University of Nottingham, Professor Richard Emes University of Nottingham and Dr David Scott Research Complex at Harwell and University of Nottingham

Summary: Viruses such as HIV are a leading cause of emerging infectious diseases and persistent pandemics. Being obligate parasites, they also depend heavily on the host cell machinery to propagate their own life cycle. Yet, surprisingly, we lack a comprehensive understanding of the structure and dynamics of the viral-human complexes that facilitate virus replication and disease progression in the cell. For example, less than 0.01% entries deposited in the Protein Data Bank till date pertain to RNA-protein (RNP) complexes formed from both human and virus components. Thus, in the proposed study, we will use an integrated structural biology approach involving a combination of experimental biochemistry and theoretical biophysics techniques (including X-ray crystallography, cryo-Electron Microscopy and Molecular Dynamics simulations) to investigate the role of the biochemically well characterised HIV TAR RNA element and Tat protein in translation initiation of HIV mRNA by determining high-resolution structure of the HIV-host Pre-Initiation Complex.

Ultra-high-field MRI for identification and assessment of epileptogenic lesions

PI: Professor Richard Bowtell, School of Physics and Astronomy University of Nottingham, Dr Andrew Bagshaw University of Birmingham, Akram Hosseini Nottingham University Hospitals NHS Trust and Professor Penny Gowland, University of Nottingham

Summary: Epilepsy is the most common serious brain disorder worldwide. The majority of patients diagnosed with epilepsy suffer from localisation-related epilepsies. Most patients achieve control of their seizures by conventional treatment strategies including medications. However, one third of patients do not achieve satisfactory seizure control with medications alone. In these cases, focal resection of the epileptogenic zone provides an excellent prognosis for seizure control. Unfortunately, current medical imaging techniques show no abnormalities in a significant proportion of patients with localization-related seizures. These patients may have subtle structural abnormalities in their brain, the most common of which is focal cortical dysplasia. MRI at ultra-high-field (7T) provides a significant increase in the signal-tonoise-ratio of the measured signals, which can be used to increase the spatial resolution of images. In addition, 7T provides easier access to important image contrasts. The aim of this project is therefore to evaluate whether ultra-high-field MRI can improve the detection and characterization of subtle structural epileptogenic abnormalities in epilepsy. The importance of this research is that the identification of a focal epileptogenic lesion in people with refractory epilepsy has crucial management implications, as surgical removal of such lesion may dramatically improve outcomes and the chance of seizure freedom.

PIs: Professor J David Brook, School of Life Sciences University of Nottingham, Professor Dylan Owen University of Birmingham and Professor Chris Hayes University of Nottingham

Summary: Myotonic Dystrophy is the most common form of muscular dystrophy in adults. It is caused by transcribed repeat expansion sequences that remain in the nuclei of patients' cells where they form distinct foci or spots, which interfere with key molecular processes. We are developing therapeutic compounds for this condition which eliminate the foci in patients' cells. This project aims to understand the underlying molecular mechanisms that lead to foci formation and disruption, using state-of the-art microscopy and image analysis, alongside novel RNA sequencing techniques. Using a combination of molecular cell biological approaches, it should be possible to determine the molecular mechanism underlying foci formation and therefore improve attempts to develop a treatment for this condition.

The effect of complex exhaust emissions on airway cell function: relevance to asthma

PIs: Dr Rachel Clifford, School of Medicine, University of Nottingham, Dr Antonino La Rocca University of Nottingham, Dr Jose Herreros University of Birmingham Dr Kevin Webb University of Nottingham, Professor Alan Knox University of Nottingham and Professor Dominick Shaw University of Nottingham

Summary: In 2013 Ella Kiss-Debrah died of an asthma attack caused by illegally high levels of air pollution in London. Globally traffic related air pollution kills 2.4 million people. Despite this governments are "passing the buck" on action to reduce environmental levels. We understand remarkably little about which constituents of vehicle exhaust are detrimental to health or the mechanisms by which they impact on lung health. In this project we combine three leading edge research programmes at the University of Nottingham and the University of Birmingham, supported by the Nottingham NIHR Biomedical Research Centre and EPSRC funding, to better understand which constituents of engine exhaust damage airway cells and how. The student will perform detailed characterisation of exhaust from three engines types representing a) low/middle income countries and freight (Diesel), b) current GDI engines and c) future hybrid engines (GDI/ethanol). An in vitro airway cell model including airway epithelial (lung barrier cells) and airway smooth muscle (structural cells) cells will be exposed to exhaust and the immune, remodelling and epigenetic profiles examined. The student will learn fundamental and novel techniques across a broad repertoire including cell co-culture, molecular biology, epigenetics, soot characterisation, epigenomics data analysis and R programming.

Multi-system effects of Very Low Calorie Dietary (VLCD) in type two diabetes (T2d) in TWO different populations

PIs: Professor Penny Gowland, School of Physics and Astronomy, University of Nottingham, Dr Susan Francis University of Nottingham, Professor Gerry McCann University of Leicester, Dr Stephen Bawden University of Nottingham

Summary: This project aims to investigate new methods of treating type 2 diabetes. Initially it will involve developing new MRI and MR spectroscopy methods for multi-organ assessment of physiology and metabolism. It will subsequently involve coordinating an experimental study of the effect of a very low calorie diet on type 2 diabetes patients from Caucasian and South Asian ethnic groups (who are expected to respond differently). This will involve setting up the experimental protocol, overseeing the acquisition of data, analysing the data and presenting the results. It will suit a physicist who has an interest in experimental and numerical approaches, and an enthusiasm to apply their scientific approach in the area of biomedicine. This project will provide important new information on the effectiveness of potential new approaches to treating type 2 diabetes, for both Asian and Caucasian ethnic groups.

Deconstructing the Role of the MOZ/KAT6A Double Winged Helix Domain in Gene Regulation and Disease

PIs: Professor David M Heery, School of Pharmacy University of Nottingham, Dr Ralf Flaig Research Complex at Harwell and Dr Ingrid Dreveny University of Nottingham

Summary: Molecular Characterisation of a DNA Binding Function Implicated in MOZ/KAT6A Driven Leukaemias Lysine acetyl transferases such as KAT6A/MOZ (gene/protein) are key players in gene regulation. These enzymes catalyse the acetylation of histones to generate a reversible histone code that signals to other gene regulatory proteins. Aberrant function of KAT6A/MOZ in human cells can have catastrophic consequences resulting in cancer or neurodevelopmental disorders. For example, recurrent chromosomal translocations involving KAT6A in bone marrow cells generate leukemogenic fusion proteins (MOZ-CBP, MOZ-TIF2) associated with childhood leukaemias. Moreover, patients born with KAT6A mutations often present global developmental delay and intellectual disability.

Our previous work characterised domains in MOZ fusion proteins that support leukemogenicity. This project will focus on a novel function we have characterised that is critical in MOZ-TIF2 leukaemia and likely also important in KAT6A patients. The aims are to use a suite of techniques to characterise the structure and function of this domain, which we can readily purify from bacteria. In collaboration with colleagues at Diamond, we aim to determine the crystal structure and understand the role of the domain in cell models. The project would present the opportunity to learn protein expression and purification, crystallography/structure determination, DNA binding assays (EMSA/ITC) site-directed mutagenesis, confocal microscopy using YFP tags, chIP and CRISPR editing, cell culture and molecular biology.

Neural adaptation to ocular misalignment; topographic maps associated with anomalous retinal correspondence

PIs: Professor Paul V. McGraw, School of Psychology University of Nottingham, Dr Denis Schluppeck University of Nottingham, Professor Irene Gottlob University of Leicester and Professor Sue Francis University of Nottingham

Summary: Anomalous retinal correspondence (ARC) is a neural adaptation to ocular misalignment (strabismus) in which non-corresponding retinal points are linked in the visual brain to support binocular fusion. This adaptation allows patients with strabismus to avoid double vision and visual confusion, but is a major barrier to successfully restoring binocular vision. ARC necessitates the reorganization of spatial maps associated with each eye under habitual binocular viewing. However, we have little understanding of where in the brain this reorganization takes place. This project will look at topological map reorganisation in a number of candidate areas. First, we will ask if the reorganization takes place in the primary visual cortex (V1), where the inputs from the two eyes are first combined. If not present there, we will examine other regions in extrastriate cortex and sub-cortical structures using ultra-high field fMRI. In the same patients, we will measure maps of space using a new approach based on the perception of motion generated when noncorresponding retinal regions are stimulated. The ultimate aim is to deliver a new understanding of the neurophysiological mechanisms of ARC, with the potential to transform how strabismus is managed and for restoring or maintaining binocular vision following strabismus surgery.

PIs: Professor Jonas Emsley, School of Pharmacy University of Nottingham, Dr Neil Morgan University of Birmingham and Professor John Schwabe University of Leicester

Summary: Blood clotting requires recruitment of platelets (specialised blood cells) to the site of injury as one of the first (of many) events that prevents bleeding. This process is highly dependent upon a protein known as von Willebrand factor (VWF) that circulates in blood which is regulated by ADAMTS13 (A Disintegrin-like And Metalloprotease with ThromboSpondin type I repeats, member 13). Clinically, human deficiency in VWF is the most common inherited bleeding disorder, whereas people with ADAMTS13 deficiency suffer from a life-threatening thrombotic disorder with a ~90% mortality rate. ADAMTS13 is a very highly specific proteolytic enzyme that cleaves only one protein (VWF) and does so at just a single site, and even then, only under very specific conditions of blood flow. The metalloprotease domain of this enzyme contains the active site that cleaves VWF and how ADAMTS13 recognises and cleaves VWF so specifically remains unclear. To understand this at a molecular level, we will ascertain the structure of whole ADAMTS13, both in free forms and in stabilising complexes with specific antibody fragments using cryo-electron microscopy. We will also analyse hereditary mutations in the ADAMTS13 gene linked to paediatric stroke and thrombotic thrombocytopenic purpura.

Defined outcomes from chaotic directions - The influence of random nanoscale mechanical stress on cancer cell behaviour and drug resistanc

PIs: Assistant Professor Mischa Zelzer, School of Pharmacy University of Nottingham, Assistant Professor Anna Piccini University of Nottingham, Alessia Candeo / Stan Botchway Research Complex at Harwell, Professor Alvaro Mata University of Nottingham and Professor Bindi Brook University of Nottingham

Summary: The microenvironment of cells plays an important part in cell behaviour and cell fate. In the past, the influence of various extracellular matrix (ECM) properties such as chemical composition, topography and stiffness on cell behaviour such as stem cell differentiation or development of diseases such as cancer or neurodegenerative diseases has been investigated. Many materials developed in this context are static, i.e. they present a single, predefined condition to the cells. Stimuli responsive materials include a dynamic element in the materials; however, even this falls short in capturing the transient nature of the ECM which is subject to constant and random chemical and physical remodelling.

This project aims to understand the random nature of ECM remodelling and its role in the development of complex diseases. We will design materials that modulate their properties randomly and investigate how these changes affect cancer cell behaviour and treatment. The project will apply a range of material fabrication (polymer hydrogels, peptides) and characterisation (rheology, AFM, spectroscopy, fluorescence imaging) approaches, device engineering to enable light stimulation, cell analysis (e.g. light sheet fluorescence microscopy, cell assays) and computational models to investigate the response of cancer cells to randomly changing microenvironments.


Summary:

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