- Total grants
- Total funders
- Total recipients
- Earliest award date
- 22 Nov 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The mechanical properties of the extracellular microenvironment influence the behaviour of fibroblasts. Solid tumours often exhibit changes in the stromal extracellular matrix (ECM) and tumour growth in turn is directly regulated by the stroma and carcinoma-associated fibroblasts (CAFs). However, it is not clear how signals are transduced from the extracellular matrix to the nucleus of CAFs or how this influences global cellular processes such as transcription. We have dentified the existence of a novel force transduction pathway from adhesion sites to the nucleus that is able to regulate cell migration and is required for tension-dependent changes in transcription. We will compare the adhesion and mechanical transduction properties of normal tissue fibroblasts with CAFs to identify how the tumour microenvironment influences force transmission. The aims of this project are: - Analyse the nucleo-cytoplasmic force coupling-dependent adhesome of carcinoma-associated fibroblasts - Identify how nucleo-cytoplasmic force coupling influences cell-matrix adhesion properties and functions - Investigate how beta-PIX regulates nucleo-cytoplasmic force transduction in CAFs - Determine the role of CAF nuclear force modulation on transcription and tumour cell invasion
Medical evangelism Colonial India 30 Jun 2016
My doctoral research entitled "A Woman Medical Missionary in Action: Dr. Edith Brown, A Case on the Christian Medical College and Hospital, Ludhiana, 1894-1947", focused on Dr.Brown as the founder of the first women’s mission hospital of Punjab. Primarily my research was on social history of women’s hospitals. It covered similar attempts of various other women medical missionaries who joined the bandwagon of opening mission hospitals exclusively for women. What caught my attention while looking up the sources was how this whole period was addressed as "Punjab and the rest", that depicted extensive missionary work intertwined with the women’s movement within and outside the Church.I am actively involved in ongoing research related to my thesis. I am extremely keen to visit the archives at Edinburgh to look up records related to women doctors of the late nineteenth century, especially the ones who joined missionary societies to work in India. A visit to the library at the Wellcome Institute will be extremely productive for my research. Needless to say, the result of this support would throw new insight on the history of missions and gender in Colonial Punjab.
The proposed research aims to develop mathematical models to help in understanding the relationship between genes, neuronal circuits, and behaviour. A nonlinear model of Drosophila courtship behaviour will be developed to guide experimental studies by providing testable predications about both neural activity and behaviour. Three projects are proposed, modelling different aspects of courtship. The first project aims to model courtship song, in particular switches between two modes of song: sine and pulse. It will be investigated whether switches in male song are related to locomotion changes in the female. The second project aims to develop and evaluate a model of courtship behaviour. A male fly courts a female by tapping, abdomen quivering, singing and licking. Switches between these behaviours seem random. A nonlinear model may account for these switches. A comprehensive computational model will be used to investigate the underlying neural basis of courtship in the fly. The third project aims to extend the model developed in the second project by including experience as a critical parameter. This bridges courtship and memory research in the fly and suggests the possibility of modulation of innate behaviour by individual experience.
Panel Sponsorship for one-day conference, 'A Life As A Lens: Using Individuals in Wider Historical Research'. 29 Aug 2014
We are organising a one-day conference for 12 September 2014 called, 'A Life As A Lens: Using Individuals in Wider Historical Research', aimed primarily at early career researches. This conference is due to have a special panel dedicated to the history of medicine. The conference will explore the methodological issues involved in research that is based on an individual or group of individuals, bringing together historians working across all periods, regions and concentrations. Rather than pa pers which focus on individuals in and of themselves, the conference will explore how historians use individuals and the sources related to them. Papers will concentrate on the challenges within this form of historical research. Can individuals truly function as representatives of wider groups, or as 'lens' through which to view broader issues, events, and ideas? Or do they obscure the past by providing a personalised or subjective picture? Among other topics, speakers will explore the role o f 'Great Men' narratives in history of medicine scholarship; the roles of resident hospital artists; and the 1960s cultural shift in 'diagnosing' child abuse as reflected through the paediatrician Henry Kempe.
Investigation of Hanta virus infection in humans 20 May 2011
The workshop will be based on a real-life case study, concerning an outbreak of Hanta virus. This infects deer mice in the USA, and is usually harmless, but a mutant form of the virus has now infected field mice. 26 people in the USA died from an unknown viral infection, and DNA technology later showed that their deaths were caused by the mutant form of Hanta virus that passed from field mice to humans. In the workshop, students will be given this case study to solve for themselves, using restriction enzymes, micropipettes and gel electrophoresis. These techniques are not normally available to us in a sixth form college.
Cryptococcal meningitis (CM) is an infection of the brain and surrounding tissues (the meninges). It is caused by a yeast called Cryptococcus and is responsible for approximately 180,000 deaths annually (26). The most effective drug is amphotericin B (AmB) which needs to be given for 2 weeks and causes dangerous side-effects. A modified formulation, liposomal amphotericin B (LAmB), may be easier to administer to patients because it can be given as a single dose, and appears to be as effective as 2-weeks of conventional AmB (12, 15, 23). This observation raises a number of questions: 1) What is the optimal dosing strategy for LAmB? I will measure drug levels and describe their relationship with reduction in Cryptococcus levels. 2) How does one dose of LAmB exert a prolonged effect? i will image the movement of LAmB in mouse brains and meninges to assess how long LAmB stays in these regions. During treatment for CM, the rate of decline of yeast in spinal fluid is highly variable (24, 25, 27). Therefore, another question is: 3) Do different groups of yeast vary in teir response to treatment? I will collect samples of Cryptococcus and characterise their survival ability in various conditions.
Clinical Characterisation of a Broad Spectrum of Genetic Variation in the General Population 30 Sep 2018
Inborn errors of metabolism (IEM) are severe and extreme changes in metabolism caused by mutations in a single gene. Recent large-scale human studies have shown that genes causal for IEM are associated with nutrients, or ‘metabolites’, in the blood. However, whether these associations cause disease or adverse health outcomes is unknown. In this project, I will use IEM genes identified in these studies to link genetic variation to clinical features in a large human population. To do this, I will assemble a list of IEM genes of interest that were identified in the literature and in large population datasets. I will then test for associations between the variants I find in these genes and a wide range of clinical features found in open-access population datasets. As the IEM genes used in this study have been associated with blood metabolites previously, linking variants in these genes to clinical features will shed light on the molecular mechanisms underlying genes and disease in the general population. Understanding how genetic variation affects disease will help identify novel therapeutic targets and enable health professionals to better manage disease risk.
Campylobacter jejuni is the leading cause of bacterial gastroenteritis and thus poses a significant health risk. The bacteria is part of the natural microbiome of the chicken caecum where it appears to function as a non-invasive commensal but in the human intestine the organism becomes invasive and pathogenic. The Ó Cróinín group have recently reported that DNA supercoiling plays a key role in inducing this invasive phenotype and that relaxation of DNA supercoiling is associated with an increase in invasion and the appearance of an invasion associated secretive. This group have also unpublished data which reveals that DNA supercoiling allows the bacteria to survive and grow under anaerobic conditions which normally do not support growth. Given the anaerobic nature of some areas of the human intestine this could indicate that relaxation of DNA supercoiling could be critical in allowing this bacteria to both secrete virulence factors as well as to survive and grow under anaerobic conditions. The aim of this study is thus to investigate and characterise the effect of DNA supercoiling on the ability of the bacteria to grow under anaerobic conditions as well as to compare the secretion of proteins by microorganisms grown under anaerobic and microaerophilic conditions
Human Fcgamma receptors (FcgammaRs) are proteins found on the surface of immune cells. They bind to antibodies, which are produced by the body, in response to infection. Some antibodies produced recognise their own tissues and are found in many diseases, including rheumatoid arthritis and lupus. It has been shown that genetic changes in the FcgammaRs are found more frequently in rheumatoid arthritis sufferers compared to healthy individuals. This project will focus on FcgammaRIIa, which is present on cells which are responsible for the destruction of many antibody-bound objects. Through a combination of cutting edge techniques, spanning physics, biology, immunology and medicine, we will uncover fundamental information within this field. This information would aim to inform the production of effective therapies to treat diseases such as arthritis, which put a huge strain on the NHS every year.
The Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a programmable RNA guided endonuclease, which is effective at gene editing in mammalian cells. These highly specific and efficient RNA-guided DNA endonucleases may be of therapeutic importance to a range of genetic diseases. The CRISPR/Cas9 system relies on a single catalytic protein, CRISPR associated protein 9 (Cas9), which can be guided to a specific DNA sequence anywhere in the genome by the substitution of a 20-nucleotide sequence, complimentary to the particular target, within a single RNA molecule (sgRNA).A number of computer programs have been developed to predict the sgRNA that cuts the intended target most efficiently with the least off-targetting. I aim to identify, design and characterise sgRNA molecules that could be used to target mutant corneal dystrophy genes by using molecular biology techniques such as in silico identification of mutations in corneal dystrophy genes suitable for CRISPR/Cas9 gene editing with in vitro testing of selected guides, design of sgRNA to target the identified mutation and comparison of sgRNA design and off-target prediction tools.
A structural investigation into the action of and resistance to ribosome-targeting antibiotics 30 Sep 2018
Antibiotics are crucial to modern medicine, allowing treatment of life-threatening bacterial infections and making many surgeries like transplantations possible. However, pathogenic bacteria are rapidly evolving to resist their effects. Protein synthesis is one of the main antibiotic targets in bacterial cells. I will use structural biology techniques, principally cryoEM and single particle image processing, to understand how both novel natural products and clinical antibiotics bind to the ribosome to bring about their inhibitory effects on protein synthesis. Furthermore, I will investigate the cause of toxicity of certain ribosome-binding antibiotics by examining how they bind to the mammalian mitochondrial ribosome. Finally, I will use a combination of cryoEM and protein X-ray crystallography to elucidate how certain ribosomal-protecting proteins form complexes with the ribosome in order to bring about antibiotic resistance. On an individual level, these studies will allow an assessment of the viability of novel natural products as suitable clinical antibiotics. More generally, they will contribute to our knowledge of how different classes of antibiotics target the ribosomes of pathogenic bacteria, and how these bacteria evolve resistance. This knowledge will help the development of methods to rationally design new ribosome-targeting antibiotics that are able to overcome or circumvent resistance.
Surgery and chemotherapy, which preferentially kills dividing cells, are the main treatments for colon cancer: a common disease in the developed world. To develop better treatments requires defining the molecular events that cause tumours to grow so that these specific aberrations can be bypassed. Mutations in a gene called Adenomatous polyposis coli (Apc) are the most common molecular change identified in colon tumours. The Näthke lab recently discovered that APC protein (encoded by the Apc gene) binds to and regulates the abundance of another protein (MINK1) with roles in cell division and movement. This raises the possibility that faulty control of MINK1 by mutated APC could explain why cells in colon tumours divide excessively and migrate aberrantly. I will investigate the function and control of MINK1. Using cells grown in dishes and also cells that form mini-gut structures called organoids, experiments will be designed to determine whether and how MINK1 is required for Apc mutations to cause cancer, and how MINK1 affects the structure of the gut lining. These issues will also be addressed in mice whose guts lack the Mink1 gene. Results will help to decide whether human colon cancer can be treated by new drugs that target MINK1.
Neuroscientific and psychological studies have found that neural activity precedes the intention to act by several seconds, indicating that our actions are predetermined by unconscious neural computation. A major shortcoming of these studies is that the acts tested are trivial (e.g. move a finger at a time of your choosing), having no real-world implications. In a series of EEG experiments, we will assess complex choices that participants make. First, participants will be asked to choose to press one of two buttons. Then, they will be asked to a) ‘reward’ or ‘punish’ a person arbitrarily, b) reward or punish a person in response to a moral act, c) choose how much to reward or punish the individual based on their action, and finally, d) choose reward and punishment allocations within social or economic constraints, to reflect real-world decision-making. This will allow us to test if there is neural activity prior to the intention to act and also to compare between consequential and inconsequential choices. The investigation of neural activity in consequential action, examined in the light of philosophical analyses, addresses an essential unanswered question of past studies, and promises to shed new light on the nature and existence of free will.
Nonsense mediated decay (NMD) is a quality control mechanism used by eukaryotic cells to destroy messenger RNAs containing incorrectly positioned translation termination codons . NMD, in combination with alternative RNA splicing (AS), also provides a potent mechanism for natural changes in gene expression in developing brain [2-5]. The main goal of my summer project will be to test the hypothesis that progressive down-regulation of an RNA-binding protein called PTBP1 during mammalian neurogenesis promotes neuronal identity by changing AS patterns and triggering NMD of multiple neural precursor-specific transcripts. I will first follow up on the RNA sequencing screen carried out in the Makeyev lab and validate bioinformatically predicted AS-NMD targets using Reverse Transcription PCR and quantitative PCR analyses of developing nervous system samples and embryonic stem cells undergoing neuronal differentiation in vitro. I will then analyse AS-MND regulation for one example showing the most robust regulation. This will be achieved by designing minigene and CRISPR-Cas constructs specific for AS-NMD promoting exons and testing these reagents in mouse ES cells undergoing neuronal differentiation or treated with siRNA against PTBP1. The results of this work should improve our understanding of the AS-NMD pathway and evaluate its contribution to neuronal differentiation.
The Effect of Acute Caffeine Ingestion on Cognitive Dual Task Performance During Assessment of Static and Dynamic Balance in Older Adults 31 May 2018
The ergogenic benefit of caffeine for sports performance has been reported extensively in younger adults (4) and recent evidence suggests benefits of acute caffeine ingestion for motor performance (5) and cognition (6) in older adults. Given such components are important mediators of postural control, it is proposed that caffeine may be an important nutritional supplement to improve balance in older adults. Studies examining the effect of caffeine on balance are sparse and focus only on static postural control (7). Such assessments give a limited understanding of balance tasks adopted during the completion of tasks of daily living, where falls are more likely during locomotory tasks requiring dynamic balance (8). Furthermore, individuals must maintain balance whilst completing secondary cognitive tasks such as communicating or crossing a road. Previous work had indicated that that completion of a secondary task can impair (9) or improve postural control but at the expense of the secondary task (10). It is unknown weather caffeine can mediate these detrimental effects. The present study aims to assess the effect of caffeine ingestion on cognitive dual performance during assessments of both static and dynamic balance in older adults.
The concept of cellular brain repair for Parkinson's disease is relatively simple - if brain cells die in this condition, then it should be possible to replace these cells through transplantation of healthy cells back into the brain. Over the past three decades, numerous animal studies and several clinical trials in human patients have shown that this concept has significant potential for repairing the brain affected by Parkinson's disease. However, poor survival of the healthy cells has limited the widespread roll-out of this cellular reparative approach to patients. Biomaterials, that is, materials that have been engineered to interact safety with living tissue for therapeutic purposes, have the potential to improve such cellular reparative therapies for Parkinson's disease. Specifically, injectable biomaterials gels have the potential to significantly improve cell survival by providing a physical scaffold and pro-survival environment for the implanted cells. Thus the aim of this proposal is to determine if biomaterial hydrogels can be used to improve cellular reparative therapies for Parkinson’s disease using animal models of the condition. We will specifically investigate the beneficial effect of biomaterials on stem cell-derived neuron cell transplantation approaches.
Optimising antimalarial treatments in sub-Saharan African children: reducing the burden of malaria mortality 31 May 2018
Sub-Saharan Africa accounts for 99% of all reported malaria cases. Children under five years are often the most vulnerable, accounting for 71% of all malaria deaths (WHO, 2017). This can be attributed to the low immunity in children which increases their vulnerability to malaria infections. Testing of drugs in children can be difficult due to ethical concerns. However, advances in pharmacokinetics (the study of how the body processes drugs) has given rise to a novel approach, which enables the simulation (in virtual clinical trials) of many clinical subjects, each possessing a unique subset of physiological parameters. Results from a previous research on pregnant women conducted by our group using the same approach was found to provide an effective dosage regimen (Olafuyi et al, 2017). In this project, we will adapt the pharmacokinetic approach to examine dosage regimen in children using piperaquine (antimalarial drug). We will also address potential drug interactions in patients co-infected with HIV, where anti-retroviral drugs can lead to the enhanced degradation of piperaquine. The study will look at data and its impact on cohorts and recommend an appropriate dosage regimen for children in sub-Saharan Africa under malarial only and malaria-HIV co-infection, which will help reduce anti-malarial resistance.
Neurotrophins and their receptors play a key role in the maintenance and remodelling of the nervous system, and defects in trophic signalling are associated with mental illness as well as neurodegeneration. To date, the cellular mechanisms regulating neurotrophin receptor bioavailability are not fully understood. Here we focus on BDNF and its receptor, TrkB, which are widely expressed throughout the central nervous system. This project will investigate the role of two novel potential TrkB regulators that recently emerged from our screens. Candidates will be expressed in HEK-TrkB cells and primary cortical mouse neurons, and (i) TrkB receptor expression levels and (ii) downstream signalling events will be investigated using both Western blotting and immunofluorescence techniques. These experiments will address whether the candidates modulate TrkB availability and activity. A better understanding of the cellular mechanisms underlying TrkB regulation may highlight potential therapeutic targets to counteract TrkB degradation and restore sensitivity of vulnerable cells to the beneficial actions of BDNF.