- Total grants
- Total funders
- Total recipients
- Earliest award date
- 02 Jan 2018
- Latest award date
- 21 Dec 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Thursday Club Salvation 17 Jan 2018
This group provides an opportunity for people over the age of 50 in the Elrig area to get together and socialise every Thursday. The funding will be used to pay the group's hall rental fees for the year.
The research laboratory of Dr. Gerald Barry is interested in understanding how viruses interact with their host on a protein level. An ongoing project in his group is examining the interaction of Schmallenberg virus (SBV), a virus of the Peribunyaviridae, with mammalian cells from different species. SBV causes congenital abnormalities in calves and lambs. The virus causes little problems in adult animals but can infect the foetus, causing malformations and abortions. Schmallenberg emerged in Europe in 2011 and is now endemic across most parts of western and central Europe, triggering small outbreaks on an annual basis. The Barry group has performed immunoprecipitation studies focusing on the NSs and the N protein of the virus and analysed interactions between them and cellular proteins. This work has led to the generation of 24 proteins of interest, that they now wish to interrogate using siRNA knockdown studies. I will focus on 5 proteins from this list, using siRNAs to knockdown their expression in mammalian cells to see if their loss impacts positively or negatively on the virus. Follow-on experiments and bioinformatic analysis will broaden our understanding of SBV interaction with cells, and help us to identify if the interactions are species specific.
alpha1-Antitrypsin, a circulating protein inhibitor of neutrophil elastase, is normally secreted by hepatocytes; the most common pathological ('Z') mutant of this protein results in the formation of an ordered aggregate (‘polymer’) that largely accumulates within the cell instead. The result is the formation of insoluble protein deposits within the liver, with a consequent toxic-gain-of-function phenotype (neonatal hepatitis and cirrhosis) and loss-of-function phenotype within the lung (early-onset emphysema, due to a protease-antiprotease imbalance). Recent data suggests that there is a partition between soluble and insoluble polymer populations within the cell. The overall goal of this study is to determine, at a molecular level, the characteristics of these polymer forms, to address the question: is there evidence for a 'decision point' that determines whether a polymer will accumulate in the insoluble fraction and thereby contribute to the liver polymer burden? To achieve this, biochemical and biophysical techniques - including SEC-MALS, immunoassays, native PAGE, and concanavalin A affinity - will be applied to alpha1-antitrypsin polymers (i) induced artificially in vitro, (ii) extracted from a mammalian model cell line, and (iii) previously extracted from a tissue sample. In addition, FRET and filter-trap assays will be used to study the kinetic mechanism in vitro.
Characterisation of the impact of the pharmacokinetics/pharmacodynamics (PK/PD) of pyrazinamide (PZA) and its metabolites on mycobacterial clearance in the context of multidrug resistant tuberculosis (MDR TB) therapy in South Africa 30 Sep 2018
Tuberculosis or TB is a serious infection, usually treated with a 6-9 month combination of antibiotics, including rifampicin, isoniazid and pyrazinamide. Multidrug resistant or MDR TB is TB that has developed resistance to, and therefore cannot be treated by, rifampicin and isoniazid. MDR TB is an increasingly important problem and treatment relys on longer, less effective, more toxic antibiotics. Improving MDR TB treatment is therefore essential. Some individuals with MDR TB will also have resistance to pyrazinamide and some won’t (likely around 50%). Recent evidence suggests that individuals with pyrazinamide resistance and those with low levels of pyrazinamide in the blood do worse on TB treatment. Despite this, no one has investigated the importance of pyrazinamide resistance or pyrazinamide blood levels in MDR TB. We plan to investigate this by recruiting 100 patients with MDR TBt. We will monitor how quickly TB is cleared from their lungs and compare this to the level of resistance to pyrazinamide and pyrazinamide blood levels for each individual. We expect to find that no pyrazinamide resistance and higher pyrazinamide blood levels lead to faster TB clearance. If this is the case this may help us to design new treatment regimens for MDR TB.
Novel role of SXL in chromatin association 31 May 2018
Sex Lethal (Sxl) is a gene which acts as a gender-switch in flies. In females, a full-length form of Sxl (SxlF) is present which initiates the start of female-specific development. In males however, a shorter form of Sxl (SxlM) is made which is unable to fulfil this function. Recently however, much research has highlighted the potential importance of similarly short proteins, termed micropeptides, in regulating pathways and protein function. As previous research has escaped SxlM due to its tiny size, it’s possible that SxlM fulfils some important role within male development which has yet to be determined. This project will investigate the importance of SxlM in the development of male physiology and behaviour, and attempt to understand how it may fulfil these roles through a novel molecular profiling technique termed Targeted DamiD, TaDa.
Haematopoietic stem cells (HSCs) are situated at the top of a hierarchy of blood forming cells and are ultimately responsible for the production of all mature blood cell types. HSCs must therefore execute a balance of self-renewal and differentiation divisions to maintain the stem cell population throughout adult life while providing enough cells to meet daily needs. Over the past decades, several HSC subtypes have been described, differing in mature cell type production and self-renewal durability. De-regulation of these cell fate choices in HSCs has been implicated in ageing and tumorigenesis and recent advances in single cell technologies have allowed greater insight into transcriptional changes driving these decisions. However, little is known about how well these profiles correspond to the proteome of HSCs and we therefore aim to construct a comprehensive protein network for HSC subtypes in order to identify key proteins involved in HSC self-renewal. The importance of candidate self-renewal regulators will be assessed by both in vitro and in vivo methods. A more complete understanding of HSC self-renewal would lead the way for more effective in vitro expansion of HSCs for research and future clinical applications such as gene therapy and bone marrow cell transplantation.
Design and Synthesis of a Bifunctional Linker for generating Haptenated Flagellin Bioconjugates for Improving Vaccine Reach and Lifespan 31 May 2018
The protein, flagellin, has been shown to enhance vaccine responses in systemic and mucosal sites, and bolster long-lived Ab responses. The ability of flagellin to migrate to mucosa opens up a strategy for delivering other antigens to the gut mucosa to elicit a more robust immune response, which is desirable for a vaccine to maximise its potential to protect. Activated iNKT-cells elicit potent systemic IgG responses but their ability to modulate mucosal antibody responses, including IgA, is less clear. If we could administer iNKT-cell agonists systemically in a way that ensures they reach mucosal sites, we would be able to examine this in depth. We now propose to use flagellin–iNKT-cell agonist conjugates to do just this, by employing flagellin as a carrier to deliver iNKT-cell antigens to the mucosa and in so doing, hopefully induce a robust mucosal antibody response. This Summer research project will focus on the synthesis of a bifunctional molecule which we will use to attach a potent iNKT-cell glycolipid agonist, which we have previously assembled, and then use the second functionality to conjugate the iNKT-cell agonist to the flagellin molecule selectively through surface-exposed Tyr residues that are concentrated in the hypervariable region of the flagellin molecule.
During the course of development, cells divide, migrate, and specialize to form major organ systems. Furthemore, among most mammals and birds, mouse cells differentiation follows a unique morphology. Understanding the molecular mechanisms underlying such process is a core issue in Biology and a curiosity in mouse, which despite differences still share fundamental properties during the process. The challenge has been addressed by leveraging current high-throughput technologies such as single cell transcriptomics. The amount and complexity of this data requires innovative mathematical frameworks that take advantage of current computational capacities. I am intersted on resolving mesodermal diversification during mouse gastrulation. Based on the premise that single cell profiles represent snapshot measurements of expression as cells traverse a differentiation process, I will use probabilistic modeling among other statistical and mathematical methodologies to reconstruct a measure of a cell’s progression through some biological process, and to model how cells undergo some fate decision and branch into two or more distinct cell types. In particular, Bayesian Inference has shown to be a useful approach to take advantage of computational resources, and to include prior knowledge into models, by providing a formal probabilistic framework that allows learning from the data in order to make predictions.
Neglected Tropical Diseases (NTDs) affect more than one billion people per year and have a severe impact on the economy of developing countries. This threat is heightened for communities affected by poverty, poor sanitary infrastructure and contact with transmission vectors or infected livestock. Chagas disease, part of the NTDs is a potentially life-threatening disease caused by Trypanosoma cruzi parasites, and is commonly spread by infected triatomine bugs. Up to 10 million people are estimated to be infected worldwide, predominantly in endemic countries such as Latin America but the disease is spreading to non-disease endemic locations such as Europe, the United States of America and Canada. Benznidazole and Nifurtimox are the only approved medicines for use by the World Health Organisation but these drugs are ineffective in treating the chronic phase of the disease and have potentially fatal side-effects. Dr Bhambra’s research group has identified a novel drug scaffold displaying antichagastic activities whist remaining non-toxic to mammalian cells. Therefore, this scholarship will include the design, syntheses and safety screening of further novel compounds with drug-like properties, and aim to deliver molecules with greater on-target potency and reduced off-target effects leading to promising compounds suitable for further preclinical investigation.
The LINC complex is a nuclear membrane protein complex, which controls nuclear stiffness. This protein complex has been found to be deregulated in metastatic breast cancer cells, decreasing cell stiffness, and therefore increasing the cells’ ability to deform its nucleus and pass through pores and restricted spaces. This project aims to characterize the LINC complex of metastatic breast cancer cells, and to study the modifications that occur in its quaternary structure when cells are treated with drugs that alter their redox potential. Because this complex is stabilized by disulphide bonds, we propose that treatment of metastatic cells with drugs that modify the redox status of the cell and cause ER stress could have an effect on the LINC complex and restore its function. Thapsigargin is a natural endoplasmic reticulum (ER) stress inducer, and this increased ER stress will trigger apoptotic signalling pathways in the cell. Function restoration of the LINC complex would allow control over metastatic breast cancer cell migration, preventing the tumour from spreading and focalizing it in a specific area. The results obtained from this study may open up new treatment opportunities and the restriction of cell migration may improve the effectivity of current clinical treatments.
Environmentally-regulated genes as venue for the discovery of new anti-inflammatory and bactericidal therapies 31 May 2018
Like many other immunological processes, inflammation is ‘plastic’ and is controlled by a wide range of factors including external conditions such as diet, socio-economical status and lifestyle. Using the Enriched Environment (EE) as model of ‘wellbeing’ and positive emotional state the host lab has shown that mice housed for 2-week in EE show an enhanced capacity to mount a pro-resolving and positive inflammatory responses and can clear bacterial infections more effectively (for more details see the full studies by Rattazzi et al. and Brod et al.).. Microarray analysis of whole blood taken from mice exposed to EE has identified a unique gene fingerprint with 8 genes being specifically up-regulated.Among the genes identified, 4 genes: Chil1 (Chitinase-3-like protein 1, CHI3L1), SRBP1A (Signal-regulatory protein beta 1A), S100A8 and S100A9 were found to be associated with an efficient inflammatory response and an increased bacterial clearance thereby contributing to host protection. Using molecular modelling we have identified new compounds that will act as agonists of the molecules described above and hence provide the same pharmacological effects of 2-weeks of ‘wellbeing’. The aim of the vacation scholarship will be to evaluate the effects of 12 new molecules (3 for each gene) on chemotaxis and phagocytosis.
Diabetes is characterized by the body's inability to regulate blood glucose. Pancreatic beta-cells regulate glucose through insulin release. Monogenic Diabetes is a rare type of diabetes caused by single gene germline mutations that make beta-cells dysfunctional. Diagnosis with Monogenic diabetes is done through genetic testing. However, similar mutations can have different phenotypes and penetrance in families, underlying the need to address the pathophysiology of the mutations ex vivo. During my PhD project, I will analyse the data available for induced Pluripotent Stem Cells (iPSCs) derived from patients with Monogenic Diabetes banked through the Human Induced Pluripotent Stem Cells Initiative (HipSci). Mutant and healthy iPSCs lines will be differentiated towards pancreatic progenitors and beta-like cells, to determine their effect on pancreas development and beta-cell function. CRISPR-Cas9 will be employed to correct the mutations. The mechanism of action of the mutants will be investigated in vitro. The function of the corrected and mutant iPSCs differentiated towards beta-like cells will be addressed in vivo. This study should contribute towards understanding the heterogeneity of Monogenic Diabetes phenotypes. In the long-term, it could help towards a more accurate detection of Monogenic Diabetes and personalized treatment.
An investigation of the reliability and utility of the Axivity AX accelerometer compared to a Actigraph GT3X+ accelerometer in healthy adults within free-living conditions 31 May 2018
The aim of this project is to investigate the validity of the Axivity accelerometer to measure PA in healthy adults within free-living conditions by comparing step counts to a gold standard Actigraph accelerometer. A sample group of 10 healthy participants will be recruited who will wear the monitors continuously for seven consecutive days. No change to the participant’s current level of activity will be required as this project is purely observational. After the data collection period, the monitors will be collected from the participants, and the data downloaded to a computer by the researcher. During the collection period the participants will also keep an activity log which will be collected at the end. Utility of wearing each monitor will also be recorded. Descriptive statistics will be used to summarise study populations demographic and other characteristics. To investigate validity of the Axivity monitor, the percentage agreement between Axivity and ActiGraph for step count will be calculated using limits of agreement (LOA). ActiGraph will be considered the criterion measure and a value close to or equal to 100%, with narrow LOA will indicate higher levels of agreement between the two measures under investigation.
Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system that causes demyelination and axonal loss and leads to chronic disability in young adults. Brain plasticity, that is the ability to adapt to damage, can limit the clinical impact of MS. Plasticity is influenced by brain reserve and cognitive reserve. Reserve mechanisms represent the brain’s resilience to damage, conferred by the brain’s pre-morbid functional and structural characteristics. Due to brain plasticity and reserve, in MS there is a discrepancy between the degree of damage and the clinical manifestations of the disease. In this PhD project, I propose to investigate (a) the relationship between brain plasticity and reserve in healthy volunteers; (b) its alteration with MS inflammation; (c) the role of reserve as a predictor of recovery mechanisms in MS patients. I will conduct longitudinal experiments, involving both healthy volunteers and MS patients using a strong behavioural paradigm to induce plasticity. Advanced functional and structural MRI will be used to quantify the amount of reserve, to identify mechanisms of plasticity occurring with behavioural training and to understand changes in energy usage with plasticity.
MicroRNAs buffering of transcriptional noise 30 Sep 2018
MicroRNAs are short non conding RNAs found in all animals and involved in most biological processes where they normally function as translation repressors. Virtually every mRNA is targeted by several microRNAs and individual microRNAa are predicted to target hundreds of different mRNAs. As modulators of translation they are often found to be components of complex regulatory gene networks, however a single microRNA generally has a relatively small impact on the network overall. Mutating a single microRNA does not normally have a large phenotypic effect on an organism. This observation has led to a hypothesis that microRNAs may act primarily by buffering the effect of transcriptional noise or environmental variability on transcription to normalize protein levels. In this work we aim to establish a system to allow the study of microRNA buffering through quantitative simultaneous imaging of a microRNA target and its protein product.
The role of an organism’s nervous system is to make sense of the world and generate appropriate behaviours. This process requires that neurons – the cells that form the fundamental building blocks of the nervous system – perform two basic tasks in parallel: First, neurons must make sense of sensory inputs, such as sight, sound and touch, to accurately represent the world. Second, neurons must use this information to inform decisions which guide behaviour. The goal of this project is to use a mouse’s response to whisker touch as a model to understand these two processes. I will use advanced microscopy techniques to record the activity of the mouse’s neurons while it makes decisions based on different objects detected by its whiskers. Simultaneously, I will modify the activity of individual neurons. If these manipulations impact the decision making of the mouse, it will give us insight into how the brain makes decisions in natural environments. Overall, if successful, this project will help to unravel the fundamental principles governing neural processing in the mammalian brain. This is one of the most fascinating mysteries of modern science, and may form the groundwork for future treatments of neurological conditions.
Development and application of simplified whole-cell models to understand complex cell behaviour 30 Sep 2018
Cells are often described as 'the building blocks of life'. As such, they are vital in a wide range of applications, from understanding complex biological processes like the immune system, to producing new drugs to combat diseases. Understanding how cells behave at a fundamental level is therefore crucial in being able to develop these research areas and thus improve society. The ways in which cells behave, however, are extremely varied and defined by complex sets of internal mechanisms. To aid our understanding of cell function, therefore, we can use mathematics and coding to 'model' key processes, for example 'how cells produce proteins efficiently'. By focussing on general details when modelling, we can not only predict elements of cell behaviour, but also apply it to different cells and contexts. At present, the Stan group at Imperial has developed a simplified model that describes how cells use energy to allocate their resources during key processes. To exploit this model, we aim to apply it to a range of contexts, for example modelling how cells produce different proteins so stably and efficiently. Consequently, we are able to probe cell function and build a framework for an enhanced understanding of fundamental cell behaviour.