- Total grants
- Total funders
- Total recipients
- Earliest award date
- 22 Nov 2005
- Latest award date
- 05 Mar 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
PhD Grant Proposal 30 Sep 2018
Older people are often classed as either experiencing ‘normal’ cognitive ageing, or ‘pathological’ cognitive ageing as a result of diseases such as Alzheimer’s (AD). However, these classifications fail to reflect the spectrum of cognitive decline that is experienced as we age. Age-related cognitive decline is a hugely important health problem; it has a profound impact on quality of life, increases the risk of depression and may herald dementia. Because of this, it is important to investigate what influences how well we age cognitively. Age itself is the biggest risk factor for cognitive decline. The comprehensive causes and mechanisms of ageing are not fully understood but we do know that the process is closely integrated with inflammation – the body’s immune response to injury or irritants. Although recently receiving significant attention, the precise cause-and-effect relationship between inflammation and cognitive ageing has not yet been fully explored. Using different techniques, this project will investigate the role of inflammation in cognitive ageing, and whether the process can explain why some people are more resilient than others. Understanding the differences in individual’s cognitive decline is critical to developing interventions to prolong cognitive health and to gain insight into diseases of cognition such as AD.
Investigating the immunomodulatory effects of extracellular vesicles derived from mesechymal stromal cells 31 May 2018
My proposed hosting group has shown that mesenchymal stromal cells (MSCs) ameliorate kidney injury in mice through paracrine effects.Their preliminary work suggests that the MSCs are entrapped in the lung following intravenous administration and mostly die within 24 hours. Host macrophages are attracted to the MSCs and are stimulated to upregulate the anti-inflammatory cytokine, IL10, which suggests they are being polarised towards an anti-inflammatory phenotype (i.e. to M2 macrophages). The main aim of my project is to explore whether extracellular vesicles (EVs) released by the MSCs are responsible for mediating their immunomodulatory effects. Specifically, I will investigate whether the EVs polarise macrophages towards an M2 phenotype. The first objective will be to use a co-culture model comprising human bone marrow-derived mesenchymal stromal cells (BM-MSCs), which have already been shown to polarise macrophages to an M2 phenotype. The BM-MSCs will be co-cultured with human macrophages using a transwell culture system, and the ability of the BM-MSCs to polarise the macrophages to M2 will be investigated using flow cytometry and quantitative reverse transcriptase PCR (qRT-PCR) to determine the levels of M1 and M2-specific markers. The effect of BM-MSC-derived EVs on macrophage polarisation will then be tested.
Pseudomonas aeruginosa is a Gram-negative bacterium that is a leading cause of many hospital borne infections. In particular recent research has identified the Type 6 Secretion System (T6SS) present in P. aeruginosa and has focused on the structure and mechanism of the system. This highly complex system allows P. aeruginosa to accurately penetrate adjacent cells and thus insert an array of toxins which can cause cell death or disrupt cellular pathways. Building on this work we would like to understand the T6SS from a statistical perspective. Understanding the spatial distribution and dynamics of the T6SS along the cell membrane of P. aeruginosa are amongst a number of different questions we hope to explore in this project. To achieve these targets we will use fluorescently tagged components of the T6SS mechanism as well as confocal microscopy of living P. aeruginosa, thus allowing for 3-dimensional reconstruction. These biological questions will be answered using a variaty of quantitative approaches. To extract important information from the image data a number of imaging and video preprocessing methods will need to be applied. After preprocessing the this data will be analysed using a variaty of statistical methdologies in order to provide a quantitative description.
Active Inference and Optimal Decision-Making 30 Sep 2018
Depression is strongly associated with a decline in cognitive function, and is seen in a high number of elderly individuals. It has been suggested that there is a strong epidemiological link between a personal history of depression and an increased risk of developing Alzheimer’s disease in later life. The key aim of this project is to use models of learning and decision-making to better link behavioural characteristics of these two psychiatric illnesses to their brain circuit substrates. We aim to reveal model-based behaviours and brain circuits that are shared with depression and different dementia profiles, including Alzheimer’s disease. We will use an adapted version of a pre-existing video game environment to examine activation of the dopaminergic midbrain, using fMRI. We will look specifically at reward prediction errors, and precision, i.e. the degree of confidence in the action an individual takes. By describing these behaviours using computational models, we hope to provide more accurate descriptions of human behaviour, the causes of such behaviours, and the specific brain regions and neural circuits that these behaviours are linked to. This may lead to earlier diagnosis of such psychiatric illnesses; therefore patients can undergo treatments earlier on in the disease progression.
Investigation into the role of RBM8A/Y14 in the development and function of megakaryocytes and platelets using a human pluripotent stem cell model of haematopoiesis 30 Sep 2018
Platelets are small blood cells, which cause blood to clot, preventing bleeding after injury. They are produced by megakaryocytes, large cells in the bone marrow. In people with low platelet counts (thrombocytopenia), life-threatening bleeding occurs spontaneously or after injury. Studying platelet and megakaryocyte development and function is important in understanding a) diseases causing thrombocytopenia, such as genetic disorders and other conditions, particularly cancer (and chemotherapy) and b) strokes and heart attacks, where platelets are excessively activated, forming clots that block vessels. Using stem cells (special cells capable of becoming any cell type) derived from adult skin or blood samples we grow & study megakaryocytes and platelets in the laboratory. We study a rare genetic disease, Thrombocytopenia with Absent Radii (TAR) syndrome, in which babies are born with very few platelets and abnormal bone formation (particularly the radius in the forearm). Our group discovered the cause of TAR, due to abnormalities in a gene called RBM8A, which helps cells control what proteins are produced; however precisely why this causes TAR is unclear. We believe our research will uncover the mechanism of this condition, helping to treat patients with TAR and improve wider understanding of how megakaryocytes & platelets develop and function.
Investigation of pro-regenerative mesenchymal subpopulations during liver regeneration using a single cell RNA sequencing approach 30 Sep 2018
Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide. The liver has a remarkable ability to regenerate following injury, however in many cases of CLD this regenerative capacity is overwhelmed. Currently the only effective treatment is liver transplantation but demand for donor organs greatly outstrips supply. New therapies are urgently required. Liver regeneration involves a complex interplay between multiple cell types, including a family of cells called mesenchymal cells. Whilst traditionally, the role of mesenchymal cells was more often studied in the context of liver fibrosis (scarring), recent studies have shown that these cells are also important during liver regeneration. Initial experiments in the Henderson lab, using a cutting-edge technology called single cell RNA sequencing (which allows the sequencing of genes in single cells), has shown that mesenchymal cells, rather than being one family of cells with similar function, are actually very varied in terms of their function, performing many different, important roles within the liver. I will use this powerful technique to identify the pro-regenerative mesenchymal cell subpopulations responsible for driving liver regeneration. Using this information, we hope to design new treatments to harness specific cellular subsets to drive liver regeneration in patients with CLD.
Historically, ribosomes have been viewed as unchanged homogeneous units with no intrinsic regulatory capacity for mRNA translation. Recent research is shifting this paradigm of ribosome function to one where ribosomes may exert a regulatory function or specificity in translational control. Emerging evidence has identified heterogeneity of ribosome composition in specific cell populations, leading to the concept of specialised ribosomes. Specialised ribosomes may therefore exhibit control and regulation over the translation of specific mRNAs, resulting in a substantial impact on how the genomic template is translated into functional proteins. Due to the emerging concept that cells can control the composition of ribosomes to regulate protein expression, it would seem highly likely that viruses could also manipulate host cell ribosome compositions to enhance the production of viral proteins. We have quantitative proteomic and ribosomal profiling data suggesting Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates ribosomal biogenesis. Firstly, we will investigate changes in composition and stoichiometry of proteins within the ribosome, driven by KSHV. We will isolate ribosomal complexes by tandem affinity purification, during KSHV infection and analyse changes by LC-MS/MS and cryo-EM. We will elucidate how these changes exert ribosome-mediated specificity to promote KSHV lytic infection using a number of cellular and molecular techniques.
Gene Therapeutic Strategy for Autosomal Recessive Spastic Paraplegia Arising From Mutations in SPG47 31 May 2018
Hereditary spastic paraplegias (HSPs) are a family of progressive lower-limb spasticity disorders characterized pathologically by degeneration in the corticospinal and spinocerebellar tracts. Spastic paraplegia type 47 (SPG47) is a subtype of HSP, caused by recessive mutations in the AP4B1 gene, leading to a significant reduction in the transcript protein levels. The gene codes for a subunit of Adaptor protein complex 4 (AP4), an essential intracellular trafficking protein in neurones. A loss-of-function hypothesis for SPG47 is backed by substantial emerging evidence, as mutations in all the other subunits of the AP4 complex disrupt the protein's normal and cause a very similar clinical presentation to that of SPG47. Gene therapy aimed at restoring AP4B1 protein expression therefore represents a rational therapeutic approach to ameliorate the disease phenotype. This project aims to design therapeutic vectors (AAV9 and AAV-PHP.B.) to express human AP4B1 gene under Chicken Beta Actin promoter. It also aims to evaluate their in vitro efficacy in cortical neurons isolated from AP4 ß-/- knockout mouse model and AP4B1 KO HeLa cell lines. If successful, the vectors can be tested in the future in animal models and eventually in clinical trials, aiming to treat SGP47 and improving patients’ quality of life.
Immunoglobulin E (IgE) is thought to be the first line of defence against parasitic pathogens, mediating immune reactions by binding to either of its two receptors, either the high-affinity FcepsilonRI receptor or the low-affinity CD23 receptors. While the IgE molecule was previously thought to exist in a primarily acutely bent conformation in solution, Drinkwater et al. (2014) found that IgE was able to exist in a fully extended conformation while Davies et al (2017) showed that omalizumab (XolairTM by Novartis) trapped IgE in a partially bent state to block its action on its FcepsilonRI receptors. The McDonnell Laboratory has derived a series of anti-IgE antibody Fab fragments, selected for their ability to affect IgE’s overall structure and dynamics and consequently to allosterically affect the binding to IgE’s receptors. In this proposed study, we will investigate how observed ligand-mediated changes in conformational dynamics manifest themselves as entropically-driven allosteric modulation. As a complement to NMR studies of ligand-mediated changes in protein dynamics, currently ongoing in the McDonnell Laboratory, direct measurements of the thermodynamic parameters of ligand binding will be performed using isothermal titration calorimetry.
Depression, anxiety and quality of life in a palliative population: a comparative study across different settings – home, hospice and hospital 31 May 2018
Palliative medicine deal with a fragile population- both in terms of the patient themselves and their families. Psychological health is often an extremely delicate topic to approach. By conducting a comparative study across different settings – home, hospice and hospital I intend to begin bridging that gap between physical and psychological care. I will conduct a cohort study to gather qualitative data on the mental wellbeing of palliative care patients, specifically measures of depression, anxiety and quality of life. Examining the relationship between symptoms depression, anxiety and adjustment disorder in a palliative population will allow terminally ill patients the opportunity to be heard. Publishing my data and statical findings introduces the possibility that end-of-life patients could improve their peers treatment and quality of life. Furthermore, by uncovering an intricate connection between a palliative patient's environment and their overall wellbeing, my research could help to produce local and national guidelines for a more tailored healthcare plan.
The regulation of gene expression is fundamental for cellular integrity and is partly achieved by the opposing action of repressive and activating histone modifications. One such histone modification is the tri-methylation of lysine 4 on histone H3 (H3K4me3), which is known to correlate with transcriptional activity. The SET1A complex is responsible for depositing the majority of H3K4me3 in mammalian cells and disrupting its function often leads to gene expression defects. However, the mechanisms by which SET1A regulates gene expression remain unknown. I will use the auxin-inducible degron system to rapidly deplete SET1A levels. A series of genomics technologies, including ChIP-seq and NET-seq will then be used to determine the effects of SET1A loss on chromatin architecture and transcriptional activity. Additionally, proteomics techniques will be used to identify the pathways perturbed upon SET1A loss, hence identifying the mechanisms by which SET1A supports active transcription and furthering our understanding of how gene transcription is regulated. This is essential for the development of novel therapies targeting genetic diseases in which the control of gene expression is perturbed.
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.
Spinal cord injury is a devastating condition that may lead to loss of limb movement, sensation and bladder control. Despite intense research, treatment is still very limited. Most research to date has focused on biochemical signalling. However, some more recent studies have hinted that mechanics might play an important role in spinal cord regeneration. Using atomic force microscopy (AFM), a cutting-edge technique which allows us to very precisely measure stiffness maps of biological tissues, we will investigate the stiffness of spinal cord tissue at various time points after injury and compare this to the stiffness of healthy spinal cord. We will test whether artificially modifying the stiffness of the damaged spinal cord or modifying mechanosensing in spinal cord cells improves regeneration of neurons after spinal cord injury. Our studies will be carried out in a cervical contusion model in rats which closely mimics the pathology seen in the human spinal cord after injury, even though the behavioural impairments the animals show are markedly less grave.
Cancers develop as a result of many interacting factors. Two such factors are cell stress and microRNA (miRNA) expression. Cell stress causes fluctuations in protein levels, which can perturb the proper functioning of the cell. miRNAs silence specific genes, and therefore can induce changes within the cell which cause them to become cancerous. However, little is known about how miRNA expression is altered. I aim to investigate a novel mechanism of miRNA regulation, which may be perturbed by cell stress. I will determine how the levels and activity of key components in miRNA biogenesis are altered in cells expressing different proteins and which have been subject to different stress conditions, using a range of in vitro, cell-based and biophysical approaches. I will also perform several screens to identify key microRNAs regulated by this mechanism, and how their expression changes with cell stress. This work will reveal new avenues for cancer therapy and help us to target cancer with a fresh perspective.
Molecular and antimicrobial characterisation of Propionibacterium acnes isolates from patients with severe recalcitrant papulopustular and nodular acne 31 May 2018
The widespread use of antibiotics for the treatment of acne vulgaris has led to the selection of Propionibacterium acnes ‘super-bug’ strains that are now resistant to first line antibiotics. Consequently, a growing number of patients are emerging with forms of acne that are non-responsive to common antibiotic therapies. As alarming, many of these patients also have extremely severe and aggressive forms of the disease, as well as resistance to oral retinoids. Characterization of the P. acnes population associated with severe recalcitrant papulopustular and nodular acne is therefore vital so we can identify new, pathogenic, multi-drug resistant lineages that may be driving this pathology. Such a study will also enable us to investigate if novel super-bug lineages of this bacterium are disseminating within the population, as well as providing an invaluable platform for the generation of skin microbiome-based diagnostics. The aim of this project will therefore be to characterize antibiotic resistant isolates of P. acnes recovered from patients with severe recalcitrant papulopustular and nodular acne, and a key goal will be to determine if strains represent new genetic sequence types circulating within the population. Another key objective will be to examine minimum inhibitory concentrations (MICs) and biofilm formation by these strains.
Measuring frailty in older rural South African population - Construction and validation of a Frailty Index 31 May 2018
Data from the HAALSI cohort from rural South Africa will be used to achieve 3 aims: To derive a Rockwood deficit-accumulation Frailty Index (FI) in this population To test whether the FI predicts mortality in the HAALSI population To compare results from the Fried frailty score and the FI A review of existing literature will inform the selection of a minimum of 30 variables for inclusion in the Frailty Index. Examples include (but are not limited to): disease diagnoses (e.g. angina, HIV), functional impairments (e.g. low gait speed, low grip strength), or biochemical/haematological derangements (e.g. low haemoglobin). Absence of a deficit scores zero; presence of a deficit scores 1. Cox proportional hazards models will be used to examine the association between the FI and time to death in the HAALSI data; unadjusted models and models adjusted for age and sex will be developed. Finally, the ability of the FI to predict 1 year mortality will be compared with the ability of the Fried phenotypic score to predict 1 year mortality in the HAALSI population. Receiver-operator characteristic curves will be developed for each score, and the c-statistic for each score compared.
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.