- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2007
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The main aim of our research is to determine the differences in the lifespan and physiology of male and female Drosophila melanogaster in response to increased levels of sugar (sucrose) in the diet. Current human diets are detrimental to health and obesogenic. The health outcomes are dependent on the sex of the individual, however the molecular and physiological mechanisms are not understood. The results of our study will help establish a Drosophila model that can be used to understand how nutrition and sex interact, which might contribute to a healthier lifestyle choices in humans leading to healthy ageing. The effects of diet on lifespan and diet-induced obesity of the two sexes will be recorded, as well as the feeding behaviour using the proboscis extension assay and blue-food assay. Gut morphology/function will also be examined since the gut appears to underlie the different response of the sexes to increased dietary protein. In particular, we will focus on age-induced hyperplasia by determining the number of proliferating cells (stained with anti-phospho-Histone 3). We will also monitor gut function by assessing the leakiness of the gut using a blue food. Finally, statistical analysis using suitable regression models will be performed in R.
This proposed research intends to investigate the brain representation of complex, multilayered three-dimensional environments in free-roaming rodents by detecting electrical neuronal activities. With the assumption that the grid cell can form a lattice representation in a volumetric space, the main goal of this project is to test this hypothesis and construct more detailed mosaic neuronal models. From the previous experimental evidence, the grid cell plays a pivotal role in distance-measuring by forming a grid-like array on a flat surface, however, how this array is remodelled in vertical or tilled surface remains debatable. In this project, rats will be allowed to explore in a giant lattice model with options of climbing up or down, dwelling forwards or backwards while looking for rewards. The neuronal activities in rat's hippocampus will be collected, reconstructed into a 3D model. If the hypothesis is to be correct, the 3D cognition map is suggested to be a multiple evenly-spaced neuron filed distributed volumetrically (figure1, D and E). Otherwise, the field might be distributed in parallel columns vertical to the ground, as the extension of the 2D hexagonal array (figure 1, C).
Identification and Validation of the Determinants of Variation in T cell Immunity in Health and in Inherited Immunodeficiency Syndromes 30 Sep 2018
Vaccination is a powerful strategy to prevent infectious diseases, by stimulating our immune system to produce antibodies. However, vaccines have not been as successful in boosting immunity against infections that require a different defence called T-cells. This problem is exemplified by tuberculosis, which causes more deaths than any other infection despite the use of the Bacillus Calmette-Guérin (BCG) vaccine, because the protection provided by BCG is variable. I aim to understand why BCG only works in some people. I will investigate the idea that differences in T-cell activation in different people are responsible for differences in the protective effects of BCG. In healthy individuals, I will test T-cell activation in response to a general stimulus. Using these data, I will develop a mathematical model to understand how variation in T-cell responses comes about. I will then In BCG-vaccinate the same individuals and test if my model explains all the variability in responses to BCG and in T-cell control of tuberculosis. These experiments may reveal the molecular switches that are responsible for differences in BCG efficacy. By testing cells from patients with genetic abnormalities in some of these molecules, I will validate their role in providing effective T-cell immunity.
The loss of protein homeostasis (proteostasis) is associated with many age-associated diseases, most notably Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Despite this, the factors that control the vulnerability of cells to proteostasis collapse with age are poorly understood. Using the nematode worm Caenorhabditis elegans as a model system, we have identified the highly conserved gene mtch-1, as a new proteostasis regulator. mtch-1 encodes a mitochondrial outer membrane protein of unknown function, the knockdown of which, enhances resistance to environmental stress, maintains cytosolic proteostasis with age, and extends lifespan. However, it is unknown how these beneficial effects are mediated. This project will determine which protein quality control (PQC) components are necessary for mtch-1 to influence protein aggregation. We will use fluorescent reporters to determine the effects of mtch-1 on the activity of PQC pathways, and perform an RNA interference screen of known PQC components to determine which, if any, are necessary for the loss of mtch-1 to suppress protein aggregation. These experiments will allow us to build a picture of the previously unexplored link between mtch-1 and changes in cytosolic proteostasis with age, thereby highlighting a new aspect of PQC that could be manipulated to promote long-term health.
Investigation of the structural and conformational preferences of ribosome-bound nascent chains using NMR paramagnetic relaxation enhancement measurements 31 May 2018
Co-translational folding is best studied by providing high-resolution structural descriptions of nascent polypeptides (NCs) as they emerge from the ribosome. This is achieved by producing snapshots of the process using ribosome-associated-nascent chains(RNCs) and developing 3D structural models by combining NMR spectroscopy as experimental restraints within MD simulations. The emerging NC is a dynamic entity that searches conformational space in its quest for acquiring its correct structure; it undergoes both transient interactions with itself and the external surface of its ribosome. This Scholarship aims to develop novel distance-based, PRE (paramagnetic-relaxation-enhancement) NMR measurements of RNCs to evaluate these transient processes. Over 8 weeks, this project will enable us to develop strategies to selectively label RNCs with the MTSL "spin-labels" at a single cysteine site, by adapting well-established RNC technology. We will study two RNCs "snapshots" which capture early folding transition for an immunoglobulin protein. We will characterise the structural properties of the modified RNCs using 2D NMR spectroscopy, and quantitate possible transient interactions/compaction events by collecting PRE measurements. We will also initiate MD simulations with the new experimental restraints that have been acquired. These approaches will advance our current 3D structural models to dissect further molecular details of co-translational protein folding.
Integrated interdisciplinary approaches to design new anti-bacterials with novel mechanisms of action to tackle antimicrobial resistance in Tuberculosis 30 Sep 2018
Tuberculosis (TB) remains a serious threat to global health. The World Health Organisation estimate that 10.4 million new cases were contracted in 2015, and that over 500,000 of those cases were resistant to at least one of the antibiotics currently used to treat this condition. The spread of such resistance is a serious concern and as a result there is a need for the development of new drugs to combat TB. Recent work has identified two classes of molecule which have promising anti-tubercular properties: tetrahydroisoquinolines and non-steroidal anti-inflammatory drugs. My project will focus on the development of new anti-bacterials from these classes of molecule while exploring the reasons behind their anti-tubercular properties. This will be achieved through a combination of chemistry and molecular microbiology, making use of both laboratory and computational techniques.
Lung cancer is the second most commonly diagnosed cancer in the UK and the greatest cause of cancer-related death. A type of this disease called non-small cell lung cancer (NSCLC) accounts for the majority (85%) of cases. T-lymphocyte cells (T-cells) of the immune system patrol the body and can recognise and destroy cancer cells by recognising mutated proteins (neoantigens) on them. Despite this, the majority of patients with advanced lung cancer die of the disease, indicating the ineffective function of the immune system. In particular, little is known about the role of a particular group of immune cells called T-helper cells that are thought to be important. In chronic infections where T-cells are constantly exposed to their targets, they become less responsive as younger cells are driven to turn into later ones more rapidly. As younger cells are lost, the body's ability to fight the infection reduces. In cancer, it is possible that mutations drive a similar problem. Using lung cancer specimens from patients on a clinical trial and animal models of cancer, we propose to study the question of whether and how mutations can paralyse the ability of T-helper cells to fight the disease.
The project would involve behavioural and histopathological studies of a mouse model of Alzheimer's Disease. The transgenic mouse, Amyloid Precursor Protein Knock-In (APP-KI) expresses human-like amyloid plaques in the absence of other APP fragments and, hence, represents the best APP model currently available. They will be injected with tau, in order to mimic the combination of pathological changes that occur in human Alzheimer's-disease-affected brains. The main goals of the project involve establishing the exact time-course over which the Alzheimer's-like phenotype develops, correlating the number of human-like amyloid plaques with the extent of the memory deficit in the APP-KI mice with and without tau, and finally establishing whether there is any underlying neuronal cell death in the tau-injected mice. The first four weeks of the project would involve a battery of behavioural tests to include Open Field activity, Novel Object Recognition, Object Location and spatial T-maze testing in order to identify behavioural changes/memory deficits in the APP-KI and the APP-KI + tau animals when compared to wild type litter-mates. Afterwards the animals would be sacrificed, their brains removed and sectioned. The brain sections would be stained and histopathological changes (e.g. amyloid plaque volume and tau filaments) correlated with behavioural changes.
Investigating prevention of cervical cancer, disease burden, and opportunities for improvement in inclusion health women (IHW) 30 Sep 2018
Cervical cancer is preventable due to screening and vaccination against human papillomavirus (HPV), the main cause of cervical cancer. However, there were 3,224 new cases and 890 deaths in the UK in 2014. By 2035, this is predicted to rise by 43% due to screening non-attendance. Living in a deprived area increases cervical cancer rates and non-attendance at screening. Inclusion health addresses needs of groups frequently underserved by health services who have worse overall health than people in deprived areas. These include homeless people, migrants, substance misusers, prisoners, and sex workers. It is likely that they engage the least with cervical cancer prevention and have the greatest need for intervention. Unfortunately, they are rarely included in cervical cancer prevention research. This fellowship will fill this knowledge gap. I will measure disease levels, engagement in prevention, and find ways to improve outcomes in inclusion health women. This is needed to eliminate cervical cancer. I will achieve this in three ways: (1) a review of existing studies on inclusion health and cervical cancer (2) a study linking information on 1.6 million migrants to cervical screening and vaccination data and (3) a survey and HPV testing of inclusion health women attending outreach services.
Inhibition in the Periaqueductal Gray 30 Sep 2018
Deciding which action to take, such as whether to cross a busy road, is a critical survival skill. Making decisions requires integrating complex information and identifying the cellular mechanisms of this process is critical for understanding how the brain computes decisions. In this project will investigate neurons that control defensive decisions in mice and focus on inhibitory neurons in the midbrain Periaqueductal Grey (PAG), which have the ability to veto defensive behaviours.The first main goal of the project is to use electrophysiological and advanced molecular techniques, such as RNA sequencing and gene knock-down, to identify the genes and ion channels that control the firing of PAG inhibitory neurons. The second goal is to determine key regulators of the activity of these neurons, in particular neuromodulators and long-range synaptic connections from other brain areas, using techniques such as optogenetics in combination with behavioural assays that exploit the innate defensive behaviours of mice. The results of this work will reveal new the biophysical principles that drive firing in a key population controlling a critical behavioural decision, and provide an entry point for understanding how pathological states such as anxiety lead to maladaptive decisions.
Cellular calcium signalling is a ubiquitous and fundamental mechanism driving many processes in cell physiology. However it carries a significant energetic cost: calcium that enters the cytosol must be removed or sequestered by ATPases. In this project we propose to explore the mechanisms involved in maintaining energetic homeostasis in the face of this energy demand. The transfer of calcium signals to mitochondria is thought to support energy production, as it upregulates the rate limiting enzymes of the TCA cycle, increasing the rate of ATP production, although extrusion of calcium from the mitochondria also carries an energetic cost. The recent development of new targeted fluorescent reporters allows detailed exploration of compartmental ATP generation, making these questions accessible. We will therefore use fluorescence microscopy and imaging of a novel mitochondrial targeted ATP reporter to measure changes in cytosolic and mitochondrial ATP in response to changes in cytosolic and/or mitochondrial calcium signals to address these fundamental questions in cell biology. It is important to understand the fundamental mechanisms of cellular energy homeostasis so that we can better understand how mitochondrial dysfunction, associated with many disease states, undermines the ability to match energy demand with energy production.
The role of E2F targets in oncogene-induced replication stress tolerance as potential new targets for cancer therapy 31 May 2018
In human cells, deregulated G1/S transcription, the transcriptional wave that commits cells to the cell cycle, is at the basis of many cancers and it is governed by the transcription factor E2F2. Oncogenes such as c-myc, deregulate G1/S transcription leading to uncontrolled cellular proliferation. We will induce expression of the oncogene c-myc in epithelial human cells, that directly leads to the increase in levels of E2F transcription. Unscheduled S-phase entry leads to replication stress and DNA damage, and thus genomic instability, which may lead to cell death or drive cancer initiation if the DNA damage repair is impaired. Paradoxically, this increased E2F-dependent transcription provides also a mechanism for replication stress tolerance to protect cells from catastrophic genomic instability. Some cancers have very high levels of replication stress, and by understanding how these cells are able to tolerate such high levels, we may be able to target these buffers for new cancer therapeutics. A large scale screen is being performed in the lab to identify these targets. I will investigate the role of one of these targets. Preliminary work in the lab and previous work in yeast suggests that the Smc5/6 complex may be such a candidate for oncogene-induced tolerance.
Computational biology aims to answer some of biology’s most complex questions using computational and statistical methods. The field has successfully identified genes involved in disease and has helped to discover drugs for their treatment. My PhD research takes this approach to understand the processes by which we age. Aging is a complex disease — characterised by the progressive loss of function in an organism over time — with huge social and financial cost. Faced with an aging population, breakthroughs in this area are desperately needed. I am attempting to do this using data collected from experiments that measure the lifespan of yeast in different environmental conditions. Whilst we are only distantly related to yeast, it is a useful model of human aging as it shares many cellular processes, but lives for a fraction of the time. Ultimately, I aim to use these data to predict the genes that cause yeast to age. Whilst a handful of aging genes have been identified, more genes are likely to contribute. I use networks and machine learning approaches to make my predictions. Going forward, these will help to deepen our understanding of aging and aid the development of treatments to eventually cure this disease.
Abnormal blood vessel formation contributes to diseases such as cancer, and is the result of inappropriate angiogenic signalling. In recent years, it has been shown that in the presence of the transforming growth factor beta1 (TGFbeta1), leucine-rich alpha-2-glycoprotein 1 (LRG1) promotes the formation of new blood vessels, via a process known as angiogenesis. Blocking the activity of LRG1 by using an antibody against it leads to reduced blood vessel growth, and thus, could be exploited to inhibit cancer growth. We aim to combine the blood vessel normalisation achieved by LRG1 blockade with affecting cancer cell deterioration. To do this, we aim to modify the LRG1 antibody vehicle, using state-of-the-art biotechnology, with a suitable fluorophore to evaluate internalisation into a cancer cell (i.e. its ability to deliver cargo), followed by decoration with a suitable toxic drug to evaluate efficiency in cells.
The overall goal of this project is to investigate whether biochemical switching and metabolic reprogramming has a role in the development of myofibroblasts and subsequent scar formation in fibrosis. Therefore my hypothesis is that in scleroderma, fibroblasts reprogram their metabolism to accommodate the enhance demand of energy required to differentiate and produce more scar tissue (ECM). And that altered energy metabolism due to dysregulated signalling networks closely linking metabolism with fibroblast differentiation are critical to the establishment of myofibroblasts and contributes to the development of inflammatory-driven scar formation and tissue fibrosis. I wish to build upon the preliminary studies and determine how energy metabolism influences the behaviour of myofibroblasts in fibrosis and ask if the pathological aspects of cell behaviour be attenuate with specific inhibitors. The three specific aims of my vacation scholarship are to examine: 1. Mitochondrial morphology and mitophagy in cultured control and fibrotic fibroblasts and assess any changes in fission and fusion using mito-tracker dyes. 2. Glycolysis and Mitochondrial Respiration in cultured control and fibrotic fibroblasts using the Seahorse metabolic flux analyser. 3. The impact inhibitors and activators of key profibrotic pathways on glycolysis and mitochondrial respiration in cultures of control and fibrotic fibroblasts.
Effects of Rab3a-Interacting Molecule 1a (RIM1a), linked to the enhancement of cognitive function, on presynaptic function and plasticity: a direct link from genes to cognition? 30 Sep 2018
Neurons communicate with each other via specialised junctions called synapses. The brain contains trillions of synapses where information is transferred and processed, which shapes neuronal network and brain function. Synaptic terminals contain small vesicles filled with neurotransmitters. When a nerve impulse invades the synaptic terminal, it triggers fusion of synaptic vesicles with the plasma membrane and release of transmitter molecules. Neurotransmitters quickly diffuse towards the target neuron, where they bind to specific receptors and evoke further electrical or chemical signalling. Very often mutations in proteins that regulate synaptic vesicle fusion lead to neurological disorders and cognitive impairment. RIM1alpha is one of the key proteins that regulate synaptic release of neurotransmitters by bringing together the key components of release machinery. Recently, a novel mutation in RIM1alpha was discovered that enhances cognitive function in humans. This "experiment of nature" represents a unique model to test how alterations in synaptic function shape high-level brain activity and cognition. In this project we aim to understand the effects of this RIM1alpha mutation in mouse neuronal model on synaptic transmission and use-dependent synaptic plasticity. We anticipate that our results will provide novel unparalleled insights into the cellular mechanisms that underlie cognitive processing in the brain.
Exploring the role of Genome Architecture in Neuronal Development using an in vitro model system 31 May 2018
The research aim is to explore the role of genome organisation and three-dimensional configuration in regulating transcriptional responses during neuronal differentiation. To do so, expression of co-regulated candidate genes during differentiation from neuronal progenitor cells (NPCs) to post-mitotic neurons (PMNs) will be identified with qRT-PCR. NPCs will be dissected from E12.5 mouse cortices and cultured in basic Fibroblast Growth Factor (bGFG). Differentiation into PMNs will be induced by adding neurotrophin-3 (NT-3). The nuclear localisation of pairs of co-regulated genes will be detected using double fluorescence in situ hybridisation (D-FISH), assessing whether these genes relocate to transcriptionally active regions, like transcription factories, or transcriptionally repressive regions, like the nuclear periphery. Results will also compare transcriptional changes in neuronal differentiation with nuclear re-organisation patterns in the expression of activity-regulated genes (ARGs), like c-Fos and Gadd45b. This will allow the identification of genome architecture changes specific to cortical development. Possible gene co-localisation, genomic-wide contacts and loci interactions will be studied with 4C technology, which combines chromosome conformation capture (3C) methodology with high-throughput sequencing.
Many proteins bind to metal ions, and rely on these interactions in order to properly carry out their function - indeed failure to do so is responsible for a number of diseases. Understanding the details of how these metal-protein interactions work and developing tools to predict their occurence in newly discovered proteins, as well as predicting sites that are created when proteins interact with one another, will aid our understanting of these diseases. Such knowledge would also allow us to engineer metal binding sites into synthetic proteins, which would have enormous benefits in biosensing, novel pharmaceuticals, and developing synthetic biological circuits. This project will focus specifically on zinc-protein interactions - creating a publicly accessible database resource of known zinc binding sites, and developing sophisticated tools for predicting the location and strength of zinc binding sites in a given protein structure, including sites that occur when two protein chains come together. Ultimately the project seeks to allow a researcher to modify a protein without zinc binding ability, to enable it to bind zinc and to reveal sites for drug design to modify zinc binding.
Childhood epilepsy affects 1 in 200 children with 20% of affected children being unresponsive to available currently medical treatments resulting in significant health morbidity and socioeconomic cost. Genetic causes of epilepsy are increasing recognised with genome sequencing, resulting in further understanding of disease mechanisms. Mutations in the Eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) gene has recently been identified to cause early onset epileptic encephalopathy and intellectual disability. These children suffer medically refractory epilepsy with significant neurodisability and there is clear medical need to develop new treatments for these children. The success of adeno-associated virus (AAV) mediated gene therapy in spinal muscular atrophy and several neurometabolic syndromes provide compelling clinical precedents to develop gene therapy for genetic epilepsies such as EEF1A2 related childhood neurological disease. Professor Schorge's translational neuroscience research group has developed gene therapies for epilepsy towards clinical trial already and we hypothesise that eEF1A2 neuronal function can be restored by AAV9 mediated gene transfer. We will use the EEF1A2 null mouse that has reduced survival to 23 days with vacuolar degeneration in the spinal cord. We will deliver AAV EEF1A2 gene therapy to EEF1A2 null mouse model and evaluate vector biodistribution and effects on nervous system histology.
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.