- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
MSc History of Science, Technology and Medicine 30 Jun 2018
My research will investigate how societal concerns around venereal disease (VD) assisted in the shaping and professionalization of gynaecology in the mid to late nineteenth century. I will be considering how medical understanding of VD shaped the emergence of gynaecology as a professional discipline. I will also be considering how moral and societal concerns about VD shaped gynaecological medicine, and the impact this had on the female body. To do this, I will be drawing on the North of England Obstetrical and Gynaecological Society collection at The University of Manchester, with particular attention given to the work of Sir William Japp Sinclair on gonorrhoea. VD, especially syphilis and gonorrhoea, remain amongst the most prevalent infectious diseases across the globe. The increasing development of antibiotic resistant strains outline how VD is emerging as a serious threat to the global community. This research will explore how VD and individuals suffering from VD were perceived within past society, and how this influenced the development of professional gynaecological medicine, with a significant attention to the gender dynamics that informed both, with concerns analogous to contemporary society.
microRNAs in Oscillatory gene networks 31 Jan 2017
MicroRNAs are key regulators of gene function that have emerged as highly represented connectors within gene networks. Current work in the field suggests that microRNAs primarily serve a role in the buffering and regulation of transcriptional and translational network motifs. Unpublished data suggests that microRNAs are found in certain network motifs, such as double feedback loops, more frequently than would be expected by chance. Dynamic gene expression is a field which has recently been shown to be important in the understanding of progenitor cell maintenance and differentiation. Modulation of dynamic gene networks by microRNAs has been shown to be able to control the timing of progenitor cell differentiation in neuronal progenitor cells. It is not currently understood how microRNAs integrate into oscillatory gene networks or if they perform similar regulatory roles in other oscillatory network motifs. Using a top down computational approach gene interaction maps will be generated for human transcription factors and microRNA target predictions. Utilizing this map potentially oscillatory gene network motifs will be identified and their interactions with microRNAs predicted. A subset of neuronal transcription factors which are found within potentially oscillatory network motifs will be selected, validated and the functional analysis of the microRNA interaction investigated.
Immunodynamics of polyparasitism 31 Jan 2017
Gastrointestinal (GI) nematode infection is one of the most common infections of man’s poorest communities (circa 2 billion). Infections are acquired early in life, chronic in nature and acquired immunity is slow to develop and incomplete leading to life long infection. This provides an infectious background that influences all aspects of health and disease. Co-infection by more than one species of GI nematode is the norm. Our current knowledge of mechanisms of resistance and susceptibility to these infections has come from well-defined laboratory model systems using single bolus high dose infections by single parasite species where sterile immunity can be generated. The present proposal will utilize two of the most immunologically well defined laboratory systems to identify mechanisms of resistance generated by more natural infection exposure i.e. repeated low dose trickle infection during concurrent infection by two nematode species reflecting those concurrently infecting man. The project is designed to identify the critical components of the immune response that influence resistance generated "naturally" to GI nematodes, from the myriad of mechanisms proposed from current laboratory studies. This will help define new and better models for future studies and a rigorous setting for developing effective control strategies such as vaccines.
Exploring the relationship between the quality and availability of primary care services and demand for emergency care. 02 May 2017
Despite the implementation of a number of programmes, crowded accident and emergency (A&E) departments and increasing unplanned hospital admissions are now two of the biggest challenges facing the NHS. There is currently a focus on policies to reduce A&E attendances through changes in primary care, despite limited evidence of a relationship between the availability and quality of primary care services and the demands placed on secondary care. The focus of this PhD is to utilise a newly available and underutilised administrative dataset of all A&E attendances in England to examine the relationship between the volume and composition of A&E attendances and the accessibility and quality of primary care services. Firstly we will develop methodology to identify A&E attendances which could be avoided with better quality primary care and attendances which would be more appropriately treated within a primary care setting. This will establish the extent of the problem and potential scope for interventions. Once we have identified the potential scope for interventions, we will assess where best to target interventions by analysing if, and how, factors of primary care services influence the demand for emergency care. Finally we will assess the potential cost-effectiveness of current interventions.
This 24-month project aims to improve the accessibility of the University of Manchester historic medical printed collections by a programme of cataloguing, conservation, academic and public engagement: Key Goals To produce high quality catalogue records for priority areas of the uncatalogued medical print collections. To make the catalogue records available online via the Library’s catalogue, Copac and OCLC Worldcat To engage a range of audiences with the collections, including medical humanities researchers and the public, through targeted channels and events.
Membrane proteins destined for lysosomal degradation are ubiquitinated within the endosome and then sorted into intralumenal vesicles (ILVs), to form the multivesicular body (MVB). This critically important process is exemplified by the sorting of EGF receptor (EGFR). MVB sorting requires ESCRTs (Endosomal Sorting Complexes Required for Transport). ESCRTs collectively recognise ubiquitinated EGFR on the cytoplasmic face of the endosome and capture it within ILVs, whilst they escape. Towards understanding how ESCRTs overcome this topological problem, we will reconstitute the process. We have identified all those ESCRTs that drive EGFR sorting, and how they bind each other. We will now reconstitute MVB sorting, using proteoliposomes containing EGFR and exploiting our full complement of baculovirus-expressed ESCRTs. We will use site-directed photo-crosslinking to map the entire process biochemically, and will complement this with further in vitro analysis of the molecular architecture within the developing ILV. Key conclusions will be verified in cells. Current ideas suggest ubiquitination is the determining factor for EGFR sorting. However, we believe instead that EGFR signalling-dependent activation of ESCRTs is decisive. We will systematically identify ESCRT post-translational modifications (PTMs) that map with MVB sorting, and test using both reconstituted proteoliposomes and in cells how these PTMs control the pathway.
Charcot-Marie-Tooth disease 1c (CMT1c) is a peripheral neuropathy that involves progressive damage to myelin, the protective covering surrounding nerve cells. CMT1c is caused by genetic mutations in lipopolysaccharide-induced tumour necrosis factor-alpha factor (LITAF). LITAF is involved in endocytosis, the pathway whereby material is internalised from the cell surface and trafficked to subcellular compartments, but its precise function is unknown. Disease-associated mutations may result in subcellular mislocalisation of LITAF and cause a toxic gain-of-function that leads to symptoms of the disease. I aim to characterise the function of LITAF and how this is altered during disease using both cultured cells and transgenic zebrafish. I will use cell biology and biochemistry techniques to characterise the cellular function of LITAF, including its dynamic subcellular localisation and influence on interacting partners. I will explore how these parameters are affected by disease-causing mutations and why. I will generate transgenic zebrafish expressing LITAF mutation and characterise the phenotype, initially focusing on changes in myelin producing cells which are relevant to the human disease. These studies will help to elucidate the function of LITAF and how it is dysregulated in CMT1c. The project will contribute to our understanding of how mutations in LITAF result in CMT1c neuropathy.
During the process of producing proteins from DNA, the localisation of intermediate mRNA is an essential regulation. Misregulation of protein activity due to mislocalisation of mRNA can adversely affect both developing organisms and adult tissues. Studies on mRNA localisation in yeast have served as a paradigm for other systems. Recently the Ashe lab have identified several mRNAs that associate together as a granule, and this granule is preferentially inherited by the new daughter cell during cell division. Interestingly, these mRNAs encode for proteins that are important for the translation of other mRNAs into proteins. Therefore, the purpose this mRNA granule inheritance may be to allow rapid growth and development of the new daughter cell. The aim of this project is to investigate the purpose of RNA granule inheritance by comparing the physiology of daughter cells that inherit RNA granules and those that do not. Also, the mechanisms of mRNA localisation to these daughter cells will be studied using NIP1 mRNA, which localises to these RNA granules during cell division. This project therefore aims to study mRNA localisation to investigate mechanisms and consequences of translation factor mRNA granule inheritance, processes which may also be conserved in other organisms.
The central dogma of biology is that DNA makes mRNA, which in turn is converted into proteins. Translation, the process of decoding mRNA into protein, and its attendant regulation, thus underpins all life, as proteins are principal effectors of biological function; they catalyse most biochemical reactions and play many structural and regulatory roles. Although translation is a generally well understood process common to all eukaryotes (animals, plants and fungi) it is becoming clear that the localisation of mRNA within the cell is also important and can affect mRNA degradation, storage and the translation process itself. This can occur within granules within the cell, termed ‘mRNA granules’, that possess various physical properties ranging from aggregates to ‘liquid droplets’. These granules are often linked to ‘stress’ conditions and can have different functions, as well as being linked to numerous neurodegenerative and musculo-degenerative diseases such as Fragile X mental retardation and Alzheimer’s. We hypothesise that there are a number of related granules with overlapping as well as specific mRNA/protein components that together endow these granules with unique functions. To address this we will comprehensively characterize these granules in yeast using a range of modern biochemical techniques, coupled with semi-quantitative proteomics and integrative bioinformatics.
Epithelial closure is a process that is frequently used to close holes or gaps in epithelial sheets. The process can be observed during wound healing and multiple morphogenetic events. The fusion of the epithelial sheets is co-ordinated by the cells at the leading edge of the sheets. These cells create dynamic actin protrusions that recognise and pair with the protrusions from the opposing sheet, and join the sheets together in a 'zippering' process. Correct alignment of the sheets is crucial to ensure that the fusion is accurate. The actions and signalling of the leading edge cells is influenced by the Jun N-terminal kinase (JNK) pathway. This pathway is known to regulates multiple genes, but its exact impact on the events occurring in leading edge is still unknown. In this project we alter the levels of selected JNK target genes and observe how this affects epithelial closure. This is done by fluorescence imaging of live and fixed Drosophila embryos during dorsal closure. The aim is to identify the key regulatory proteins and determine how they control actin protrusions on the leading edge. This research will further our understanding of the events during epithelial closure, and has applications in treating developmental defects.
Genome-wide association studies (GWAS) have been used to great effect to identify genetic variants that predispose to rheumatoid arthritis (RA). 90% of associated variants are non-coding and thought to be involved in transcriptional regulation, but their functional role has been under explored. I will perform functional characterization of RA risk loci with the aim of translating GWAS findings into biological disease mechanisms and suggesting therapeutic targets. My key goals are: 1. To identify the genes that cause RA. I will identify chromatin interactions between RA loci and their targets using capture Hi-C in primary CD4+ T-cells and synovial fibroblasts from RA patients. I will explore whether associated SNP genotypes are correlated with differential expression of the genes they interact with. 2. To elucidate the mechanism by which RA-associated SNPs alter their target genes. Regulatory elements containing disease-associated SNPs will be identified in primary cells from patients and their functional importance will be verified using CRISPR/Cas9 genome editing. 3. To translate research findings into patient benefit. Identified causal genes and pathways will be intersected with known drug targets to identify existing drugs whose safety and efficacy has been proven in other diseases and which could potentially be re-purposed to treat RA.
"A diverse and inclusive public involvement community is essential if research is relevant to population needs and provides better health outcomes for all" (NIHR). Situated in the heart of a vibrant NHS and University research environment, a diverse patient population and communities with some of the poorest health outcomes in England, our team will deliver a 5 year programme of exceptional engagement, within the context of Greater Manchester’s devolved healthcare system. Based on our track record, knowledge and strengths, we will boldly experiment, learn from and reflect on, methods of working with people that address issues of social justice in health research. Our locally embedded long-term programme of activities will combine Research-driven, arts-led approaches focusing on particular groups and scaled up to national audiences Listening, responsive and relationship projects Support for researchers and development of young and diverse engagement talent Celebrating our communities who drive research Sharing our learning far and wide, including through income generation methods Thus generating more informed and inclusive health research, and people supported to learn, question, and enabled to actively contribute to such research. Underpinned by significant organisational changes, including the launch of new business model maintaining our not-for-profit status, a communications overhaul, income generation and more efficient processes, we will enhance our reputation as pioneers in our sector, influencing positive change in people, research and practice. Ultimately, we aim to be recognised as an innovative centre for excellence in engaged health research, and a leading practitioner in the UK working with underserved audiences.
Vacation Scholarships 2017 - University of Manchester
Kidney disease affects 10% of the global population and glomerular disease is the leading cause of kidney failure. Glomerular capillaries filter the blood across a specialised filtration barrier comprised of endothelial cells, podocytes and an intervening glomerular basement membrane (GBM). Podocyte adhesion to the GBM is essential for barrier integrity and ultimately for kidney survival. Using proteomics and ultrastructural analyses we have expanded the molecular landscape of cell-matrix adhesion in the glomerulus and have identified GBM defects and podocyte protrusions into the GBM as novel morphological features of early disease. However a mechanistic understanding about altered GBM and secondary effects on podocyte adhesion remain unclear. I now hypothesise that that cell-matrix interactions in the glomerular capillary wall are critical to counterbalance intracapillary forces and if disrupted there is a cascade that leads to glomerulosclerosis. I will define molecular mechanisms of glomerular force regulation in cell and mouse models of glomerular disease. This proposal will have impact by defining mechanisms of capillary wall homeostasis and by identifying therapeutic targets to treat chronic kidney disease.
How prions form spontaneously without underlying infection or genetic change is poorly understood at the molecular level, yet if we are to develop effective preventative measures for human and animal amyloidoses, this mechanism must be established. Of particular importance is identifying what can trigger this event. One strong possibility is that oxidative damage of the non-prion form of a protein may be an important trigger influencing the formation of its heritable prion conformation. This project will examine how an oxidized protein goes on to form a prion using the yeast [PSI+] and [PIN+] model prions. The specific goals of the project are: i) to test whether methionine sulphoxide reductases (MSRs) can protect against spontaneous prion formation using MSR mutants and oxidative stress conditions. ii) to determine whether methionine oxidation can occur on nascent ribosome-associated polypeptides during protein synthesis. iii) To examine whether antioxidants localise to ribosomes to protect nascent proteins against oxidation. Additionally to determine whether antioxidants localize to the sites of protein aggregation as part of the cellular antioxidant defences
In order to make this unique text available to a wider scholarly community, I will produce a critical edition with accompanying English translation and a commentary that considers the Syriac Epidemics within the context of late antique Alexandrian medicine. I already possess a copy of the text, the original being preserved in the library of the Syrian Orthodox Patriarchate near Damascus (Syr. Orth. Patr. MS 12/25). The study will address the following questions: what is the nature and genre of t he Syriac Epidemics (translation, original commentary, lecture notes)? who was its author and translator? when was it composed? what does it contribute to the study of late Alexandrian medicine? what is its relationship to other extant commentaries on the sixth book of Hippocrates' Epidemics (i.e. those of John of Alexandria and Palladius)? and how did it influence later Syriac authors? A critical edition of the Syriac Epidemics would answer questions of dating and authorship. This would allow u s to understand its position within late antique medicine and to trace its influence in the Greek- and Syriac-speaking world. The text contains roughly 50,000 words and I estimate that in edited form, text and translation would amount to some 400 pages.
Understanding the biological mechanisms leading to poor outcome in melanoma of the elderly population and developing secondary prevention strategies 19 Nov 2015
Incidence and mortality rates in melanoma are highest in the elderly. Age is an independent adverse prognostic factor. Even when old and young patients present matched prognostic criteria, old patients are less likely to survive. This project will identify the mechanism(s) underlying poor melanoma survival in the elderly; and will develop melanoma progression prevention strategies. 1)We will study if the elderly are more vulnerable to melanoma; testing whether skin of mice/humans presents an a ltered inflammatory response to ultraviolet radiation(UVR); whether old skin is less able to repair UVR-induced DNA damage; and if aged cells in the microenvironment contribute to melanomagenesis. 2)We will investigate if tumours in the elderly are inherently more aggressive by integrating salient epidemiological, clinical data with immunological and genetic criteria from 400 young/old high-risk melanoma patients with favourable/unfavourable prognosis. We will overlay deep-targeted sequencing of genes driving progression and the patterns of interaction of neutrophils, macrophages, dendritic cells and lymphocytes in the tissue of high-risk patients to investigate host response in young and old patients. This will reveal prognostic categories integrating multidisciplinary data points and will inform biology. C)We will test adjuvant rationales to prevent melanoma progression in the elderly at high risk of death.