Sheffield Institute for Nucleic Acids (SInFoNiA) has a wide variety of PhD positions available across the Institute. If you are interested in doing a PhD with the institute, please read the information below and contact the host group directly.
UPGRC Scholarships for Medicine, Dentistry & Health
Project: This studentship is focused on understanding the molecular basis of ribosome biogenesis and localisation in neurons, with the aim of opening up new avenues for intervention in disease. You will be part of a brand new, multidisciplinary collaboration between the Thomson Lab at the Sheffield Institute for Nucleic Acids (SInFoNiA) and the Twelvetrees Lab in the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield.
Neurons form complex extended cellular structures. For example, motoneurons, have cell bodies in the spinal cord whilst extending axons down to the muscles of hands and feet. It is now established that axons use local translation, allowing rapid alteration of the proteome in response to environmental changes during development or injury. However, the local translation machinery must itself reach the distal axon using axonal transport mechanisms. For a metre long axon this can be many days or even weeks and defects in transport are observed in many neurodegenerative conditions, including Alzheimer’s, Parkinson’s, Huntington’s and ALS. There can be no local translation without ribosomes; the goal of this project is to understand for the first time how ribosomes are localised to axons.
This project represents a truly unique opportunity to integrate cutting edge in vitro models of neuronal systems with biochemical & biophysical approaches to explore the molecular basis of ribosome biogenesis and localisation in neurons. The two research groups linked to this project encompass unique expertise in both ribosome and neuronal cell biology, creating a new opportunity to approach this fundamental unanswered question. You will be trained in advanced, real-time imaging and analysis, cell biological (primary and stem cell derived neuronal culture) and biochemical approaches, including state of the art next generation RNA-Protein crosslinking strategies (e.g. CLIP and CRAC). There is also potential to develop super-resolution (PALM/STORM) and CRISPR/Cas9 genome editing approaches to support the project. This research will provide fundamental insights into axonal transport, with translational outcomes for neurodegenerative diseases.
More information and apply online: https://www.twelvetreeslab.co.uk/join
Application deadline: 23rd January 2019
MRC DiMeN DTP studentships
From single-molecule to synchrotron: New tools for investigating the molecular mechanisms of Aicardi-Goutières Syndrome and other aberrant DNA diseases
Project: This studentship is focused on developing new biophysical tools to understand the molecular basis of aberrant DNA diseases. You will be part of a new, multidisciplinary collaboration between the Sheffield Institute for Nucleic Acids (http://genome.sheffield.ac.uk/) at the University of Sheffield, and Diamond Light Source Ltd (https://www.diamond.ac.uk/Home.html). As such it is likely the project will attract an enhanced stipend (as an iCASE award).
A major challenge to genome stability is the presence of small amounts of RNA interspersed within DNA. Recent studies report the levels of ribose incorporation in mammalian genomes to be >1 million nucleotides per day, making it the most frequent source of cellular DNA damage in eukaryotes. This aberrant RNA must be removed from the DNA. The human enzymes responsible for this are RNAseH1 – which recognises runs of at least four ribonucleotides), and RNAseH2 – which can detect a single ribonucleotide, hydrolysing the 5’-phosphodiester bond leading to its removal. RNaseH2 is formed from three polypeptides; RNAse H2A, H2B, and H2C. Single mutations in all these subunits have been found in patients suffering from Aicardi-Goutières Syndrome, an inflammatory disease effecting the brain and skin. Additionally, we recently reported that accumulation of DNA/RNA hybrids cause neurodegeneration in motor neuron disease and frontotemporal dementia (1). The goal of this project is to understand how these crucial enzymes locate ribonucleotides (one additional oxygen atom) within a vast sea of normal DNA and the effects of disease-causing mutations on this process.
More information and apply online here
Why do multiple pathogenic viruses including HIV, Influenza, Ebola, Herpesviruses and Adenovirus target the cellular transcriptionmachinery?
Project: Viruses frequently hijack cellular processes as part of their life cycle. A recent proteomics screen revealed a core of mammalian proteins which are targeted by multiple viruses, defining four critical cellular nodes in viral infections (Nature 487:486-490). One of these proteins, hnRNPU, was further shown to inhibit the influenza polymerase activity and replication of vesicular stomatitis virus. Additionally, hnRNPU targets viral proteins from Ebola virus, Herpes Simplex virus and Kaposi’s Sarcoma-associated Herpesvirus. Independently overexpression of a fragment of HNRNPU was shown to suppress HIV1 replication (Mol Cell 23:597-605). The cellular function of HNRNPU has remained enigmatic, though recent work suggests it plays a role in chromatin organisation ( Cell 169:1214-1227). We have now identified a critical role for hnRNPU in transcription in human cells. In this project you will investigate the interplay between viruses and HNRNPU in the context of cellular transcription and chromatin organisation. This work may lead to new therapeutic strategies in the future for treatment of viral infections. The two laboratories involved use a wide range of cutting edge techniques and training would be provided. These include CRISPR engineering of mammalian cell lines, genome wide approaches to gene expression analysis such as CHIP-seq, mNETseq and iCLIPseq combined with bioinformatics analysis of large scale datasets. We also make full use of proteomic and microscopy techniques to understand the fundamental processes of gene expression in the context of viral infections.
More information and apply online here.