State primary research question and where appropriate the primary hypotheses being tested The hypothesis is that the m6A modifications have a role in the dynamic regulation of cellular and viral gene expression in the context of the integrated stress response and other antiviral pathways. The aim is to explore this hypothesis by generating human lung cell lines that are depleted in m6A writers, readers or erasers in combination with infection with influenza A virus or SARS-CoV-2. Importantly, these respiratory viruses have different replication strategies and interactions with the host cell. Viral replication in the context of modulating the m6A system and mutations in the viruses that sensitise them to the innate immune system will be analysed. The most robust phenotypes will be subjected to an unbiased (genome-wide) profiling of mRNA expression and translation with the outcomes functionally validated.
Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.
Acute cartilage lesions, which can cause disability and progress osteoarthritis , are a significant clinical problem. The poor self-hearing capacity of the cartilage has prompted strategies to repair damaged articulating surfaces with surgically-implantable, engineered osteochondral constructs that provide a fill thickness repair that seamlessly fuses with the subchondral bone. A major hurdle in creating engineered osteochondral tissue is in replicating the distinct microenvironmets of bone and cartilage in a single continuous construct. This interdisciplinary project takes a new approach to osteochondral regeneration by engineering materials that mimic the native osteochondral tissue by spatially controlling the cellular regulation of oxygen via hypoxia inducing factor (HIF) stabilisation. Our objective will be to utilise PEGDA/hyaluronan-based hydrogels, tissue-specific growth factors and of human mesenchymal stem cells (MSC) in a single, continuous construct. We will then use a combination of biological and materials engineering methods to assess region-specific bone and cartiliage tissue formation. Translational aspects will include testing constructs in an osteochondral defect in a small animal model. We aim to deliver a new tissue engineering strategy for osteochondral regeneration by mimicking the microenvironmental conditions of native tissue, particularly oxygen pressure, to develop successful therapies to treat cartilage lesions. An ambitious versatile student will gain skills i MSC isolation and culture, qRT-PCR, histochemical and immunostaining techniques, microCT, Raman spectroscopy and small animal surgery. Objectives: year1/2-incorporate HIF mimetic gradient into scaffolds, Year2/3-demonstrate osteochondral tissue reformation in vitro, Year3/4-animal model surgery and evaluation of healing.
One important step in forebrain development is the establishment of a stereotyped dorsal pallium (giving rise to cortical excitatory projection neurons) and the ventral subpallium (producing all telencephalic inhibitory interneurons). This determines the initial excitatory/inhibitory balance of progenitors and imposes the future size of the brain hemispheres. Although the signals controlling this DV organisation and the downstream effectors driving differentiation and morphogenesis are conserved across vertebrates, little is known on the spatiotemporal modulation of these players across species. Yet, this modulation is a motor of evolutionary divergence in brain complexity. This project aims to understand the evolutionary spatiotemporal modulation of signalling networks during early telencephalon development. Under the supervision of CH, the student will analyse the dynamics of Hh and Wnt signalling activity along the DV axis in zebrafish, mouse and human telencephalon from onset of neural closure to early neurogenesis. This work will combine in situ staining and transcriptome datasets from tissue and from mouse and human 3D culture. The 3D culture will be exposed to polarised signals (Hh or Wnt) using biomaterial (cryogels) optimised by the BN team. Under ZH supervision, the datasets will be used to identify a restricted set of parameters describing the central components of the signalling network at play and to construct a dynamic model of spatiotemporal telencephalic DV organisation. This model will generate the behaviour of the three species characterised above as well as deliver predictions on the signalling dynamic across evolution. Some of these predictions will then be verified by the student in CH lab, by tissue staining and functional experiments in mouse and fish. Both sides of the proposal will be run in parallel, will deliver novel findings and develop a practical/theoretical dynamic framework that will have a lasting impact on the field of developmental neuroscience.
Sophisticated research techniques have been used to show that it is possible to extract detailed information about the targets of drugs and target responses to drugs. At present, achieving this sort of information in a routine clinical setting is not practical. The proposal here is designed to exemplify a new technology that will ultimately satisfy the clinical need for this type of information. It is anticipated that the general use of the technology to be developed will impact broadly on the application of diagnostics to clinical decision making. The key contribution will be to defining which patients should receive which drugs - the personalised medicine agenda.