- Total grants
- Total funders
- Total recipients
- Earliest award date
- 31 Jan 2017
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Optimisation of carrier materials for the delivery of olfactory ensheathing cells in spinal cord injury 27 Apr 2017
Transplant-mediated repair is a promising method in spinal cord injury (SCI) treatment. This involves transplanting therapeutic cells that promote nerve regeneration at the site of injury. For SCI, one promising therapeutic cell type is olfactory ensheathing cells (OECs). These have been shown to remyelinate demyelinated axons and promote new synapses following injury. They are also easily accessible clinically via trans-nasal endoscopic biopsy, and compelling pre-clinical evidence means that they are now close to being formally tested as part of a first-in-man clinical trial. However, currently these cells are delivered as a simple cell suspension, and this is unlikely to be optimal for creating a permissive and optimised repair environment. Thus, the objective of this project will be to develop and engineer optimised biomaterial scaffolds for OEC delivery. In doing so, it is hoped that a permissive 3D extracellular environment can be created, and the phenotype and behaviour of OECs optimised for spinal cord repair. Promising prospective biomaterials include fibrin, collagen and collagen-fibrin blends. To this end, we will investigate the effect of these promising carrier materials on OEC survival and phenotype, particularly with a focus on changes they may cause on 3D cell morphology.
In this project I will test the hypothesis that oxytocin expression and development of oxytocin-expressing neurons are altered in zebrafish with mutations in the ASD risk genes cntnap2 and chd8. I hope to find evidence for the sleep modulating effects of oxytocin, and posit whether deficiencies in oxytocin signalling pathways may contribute to sleep disorders in autism mutants. I will examine oxytocin mRNA levels across the day/night cycle for both wild-type and mutant fish established in the Rihel lab. I will then analyse the pattern of oxytocin expression in the brains of mutant embryos and their wild-type siblings. From the findings in related studies with cntnap2 mutant mice and the Rihel lab zebrafish models of autism (see references  and ), I expect to see an alteration in the amount of oxytocin mRNA for day/night between the wild-type and mutant embryos, and a change in the number of neurons expressing oxytocin. If such changes are found, they could explain the sleep phenotype observed in cntnap2 autism mutants, and elucidate a link between neuronal circuit dysfunction and behavioural perturbation in this animal model.
The putative propriospinal contribution to feedforward control mechanisms during skilled grasp 27 Apr 2017
The corticospinal pathway is the major direct pathway contributing to hand and motor function, after stroke or spinal cord injury this pathway can become irreversibly damaged. However, other parallel pathways may still function and are accessible to the motor system. The propriospinal network is an interneuronal system that is located at the mid-cervical levels (C3-C4), which transmits and alters descending commands for targeted reaching and grasping. Lesion studies have illuminated the role of this system in the recovery of reach and grasp movements.The aim of this project is to investigate the role of this connection in healthy humans. Specifically, our objective is to show the contribution of this system in feedforward grasping mechanisms. We will employ a motor task that involves grasping an object between the index finger and thumb where the task demands change prior to contact. Paired low-intensity peripheral nerve stimulation (PNS) and transcranial magnetic stimulation (TMS) will be used to probe the propriospinal modulation of corticospinal output during the task. Studying the propriospinal system in healthy humans will show how motor commands are updated at a spinal premotoneuronal level and could provide a novel pathway to target for neurorehabilitation after lesions of the central nervous system.
Regulation of microglial phagocytosis 30 Sep 2018
Microglia are the brain's immune cells. They constantly survey the brain to search for invading micro-organisms, unwanted molecules (such as amyloid plaques in Alzheimer's disease) or dying cells, but also play a key role in sculpting the circuitry of the brain by removing unnecessary cells and synapses during development. The mechanisms by which microglia constantly move their processes to survey the brain, and then remove invading micro-organisms, plaques, cells or synapses, are poorly understood. I will use 2-photon and confocal imaging techniques to investigate these events, taking advantage of recent discoveries from the Attwell lab which have revealed the importance of microglial potassium channels and purinergic receptors in controlling these events.
Structural and Biochemical Characterisation of early Nascent Chain folding on the Ribosome 30 Sep 2018
Formation of the correct tertiary structure is essential for protein function and all cellular biological processes. In vivo proteins are synthesized on the ribosome and can begin to fold co-translationally. The presence of the ribosome as well as the vectorial emergence of the nascent chain results in major differences between the folding of proteins in isolation and on the ribosome, yet there are relatively few studies on the folding of nascent chains on the ribosome. I aim to understand the early events of protein folding on the ribosome, in particular the structure and dynamics of the nascent chain as well as its interactions with the ribosome, using a hybrid of structural biology methods and biochemical techniques. Specifically, we will use NMR to gain residue specific information on nascent chain dynamics within ribosome nascent chain complexes, and cross-linking mass spectrometry to investigate nascent chain interactions. These studies will be crucial to identify any conserved mechanisms of co-translational protein folding as it occurs on the ribosome. Additionally, this study will aid in our understanding of how the ribosome is able to prevent misfolding which is linked to a broad range of devastating protein misfolding diseases.
The role of the Trem2 R47H mutation in the development of Alzheimer disease phenotypes in APP knock-in mice 31 May 2018
The field of research into Alzheimer’s disease is lacking a transgenic mouse model which shows progressive degeneration like in humans. Recently, there has been increased interest in the involvement of the immune system of the central nervous system, particularly microglia, which co-localise with amyloid-beta plaques, potentially limiting toxicity. TREM2 is a protein expressed by microglia and the R47H mutation is an identified risk-factor for Alzheimer’s disease. We propose that combining this microglial risk-factor with raising amyloid beta in APP knock-in mice may exacerbate the Alzheimer's phenotype, potentially leading to tau pathology. Initially I will be taught to perform whole-cell voltage-clamp in brain slices. I will then use a novel TREM2(R47H) knock-in mouse and examine variables previously reported as altered in transgenic APP/PSEN1 mice (and confirmed in APP knock-in mice, unpublished). In particular I will record spontaneous and miniature excitatory postsynaptic currents, the frequency of which is dependent on the probability of glutamate release and number of synapses; the amplitude dependant on the number of postsynaptic receptors. These experiments will help to elucidate the effects of microglia in early synaptic changes involved in AD and will provide initial characterisation of the TREM2 mice that will be crossed with APP knock-in mice.
Investigating notch signalling in patient-derived models of familial Alzheimer's Disease. 31 May 2018
Alzheimer's Disease (AD) is characterised pathologically by extracellular plaques composed of Abeta peptides, which are generated by the successive proteolytic processing of the amyloid precursor protein (APP) by multiple enzymes including the gamma-secretase complex. Human genetics supports a causative role for Abeta in AD: mutations and gene duplications in APP cause familial AD. Further, mutations in PSEN, which forms part of the gamma-secretase complex, are also causative of fAD. However, substantial clinical heterogeneity exists in fAD patients with PSEN1 mutations, the molecular basis of which is not well understood. Our hypothesis is that differential processing of non-APP substrates of gamma secretase may contribute to neurodegeneration in fAD. The aim of this project is to investigate the processing of non-APP substrates of gamma-secretase in fAD, using induced pluripotent stem cell-derived neurons from 7 fAD patients with mutations in APP and PSEN1 and age/sex matched controls. Specifically, we will use western blot to analyse the notch pathway in fAD and control lines and understand if this pathway is dysregulated in AD. This project will allow us to determine if the processing of non-APP substrates of gamma secretase is altered in fAD patient cell models, forming the basis for further mechanistic studies.
Does ROCK-dependant actomyosin activity kick-start nuclear descent during inter-kinetic nuclear migration in the mammalian neuroepithelium? 31 May 2018
In the posterior neuropore (PNP), actomyosin-driven apical constriction reduces the apical surface area of neuroepithelial cells, aiding neural fold apposition. This constriction is superimposed on changes in apical dimensions due to interkinetic nuclear migration (IKNM). Regional IKNM regulation is believed to alter PNP architecture, but the degree to which IKNM is linked to force generating apical constriction is unknown. The host lab recently showed that inhibiting the actomyosin-regulating Rho-associated protein kinase (ROCK) produces an atypical bimodal distribution of apical dimensions. This, alongside heterogeneous phospho-myosin light chain (pMLC)II staining, suggests only a subset of neuroepithelial cells are actively constricting at any one time. We hypothesise: ROCK-dependent active apical constriction at the end of mitosis initiates neuroepithelial nuclear descent in IKNM. To address this, I will use CD1 mouse embryos to: Compare apical dimensions and pMLCII immunofluorescent staining of neuroepithelial cells in M phase, G1, and intervening phases by confocal microscopy. Establish the time course of apical area changes and pMLCII staining following ROCK inhibitor treatment. Determine if apical area changes induced by ROCK inhibition is cell cycle phase dependent. Produce descriptive 3D in silico models of nuclear movements and apical dimensions for neuroepithelial cells with/without ROCK inhibition from confocal images.
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.
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.
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.
The pathogenesis of tuberculous meningitis 30 Sep 2018
Tuberculosis is an infection affecting people in many countries throughout the world. In some cases the infection can occur in the lining of the brain (the meninges) leading to a condition called tuberculous meningitis. This is particularly dangerous when the immune system is also suppressed by infection with Human Immunodeficiency Virus (HIV) which is also a common problem worldwide. In this context 40% of patients with tuberculous meningitis will die. When tuberculous infects the brain, the body’s own immune system is activated to fight the bacteria. This is usually helpful, but often the immune system goes into overdrive, causing more damage to the brain than the bacteria itself. This research aims to find out exactly what happens when the immune system works hard to fight the bacteria. The experiments will isolate the building blocks within the blood which dictate which molecules are involved in fighting the infection. We will discover what happens in the immune system at different points during the patient’s illness and treatment. In doing so we hope to find targets for new medicines to control the immune response therefore in the future reducing the number of people who die or are disabled due to tuberculous meningitis.
Evidence from a number of epidemiological and clinical research studies have demonstrated a robust link between child language and later social, emotional, and mental health (SEMH), which impacts children’s educational experience and increases the risk of poor mental health in adulthood. An effective intervention strategy requires an understanding of the mechanisms that underpin the link between child language and later SEMH, which remain unclear. The proposed research will investigate the hypothesis that the ability to regulate emotional responses mediates the link between language ability and later SEMH in late adolescence (ages 18-21). The proposal’s key goals are 1. To determine the influence of language ability on temporal distancing success, 2. To identify cross-sectional developmental differences in temporal distancing success, and 3. To evaluate the test-retest reliability of the temporal distancing experimental paradigm. Finding a significant association between language ability and emotion regulation success would identify emotion regulation behaviours as the more proximal target for intervention strategies for SEMH concerns in adolescence. The temporal distancing paradigm has yet to be evaluated in a test-retest comparison, and reliability estimates will advance understanding of the developmental relationships in emotion regulation. Keywords: mental health; language disorder; adolescence; emotion regulation; temporal distancing
CoAlation is a novel post-translational modification to proteins whereby Coenzyme A is covalently attached to proteins. It occurs as part of the oxidative stress response as an alternative mechanism to protein glutathionylation. It is specifically a modification of enzymes involved in cellular metabolism and protects catalytic thiol groups on active site cysteine residues from irreversible damage by reactive oxygen species and reactive nitrogen species. Applying oxidizing agents to cells results in induction of apoptosis. Such agents also induce protein CoAlation. The aims of this project are to monitor induction of apoptosis in HEK293 cells in response to treatment with oxidizing agents using anti-PARP3 and anti-Caspase 3 Western blot and Fluorescence-activated Cell Sorting and to analyse the pattern of CoAlation at different stages of apoptosis using anti-Coenzyme A Western blot.
Developing a behavioural task for measuring the ability of listeners to perform auditory scene analysis. 27 Apr 2017
The auditory brain separates simultaneous sounds arriving at the ear into identifiable and localisable sources by a process known as Auditory Scene Analysis (ASA). The two steps that are involved in ASA are i) segregation of the simultaneous auditory information and ii) the integration of the sounds from the same source into one stream. To understand how these two steps are connected and how different auditory cues interact to shape the scene, this project will develop a behavioural task and analyse the performance of human listeners. A target vowel will be presented alongside with a distractor vowel, and human listeners will identify what the target is. Listeners will only be able to identify the target if they can separate the two sounds: changing the location and pitch of target and distractor will help this. In order find out whether the separation of competing sounds is facilitated by the formation of perceptual streams, the vowels will also be presented as part of a sound sequence. Our hypothesis is that the ability to identify a target vowel will be improved by the formation of two perceptual streams. The long-term goal is to develop a behavioural paradigm suitable for humans and animals.
Integrative and conjugative elements (ICEs) are mobile genetic elements present in both gram-positive and gram-negative bacteria. They mostly reside in the host chromosome and under certain conditions, will excise and transfer to a new host via the conjugation machinery. ICEs have been found to provide the host with a wide range of phenotypes, including antibiotic and heavy metal resistance and the ability to colonise a eukaryotic host, promote virulence and biofilm formation. The ability of ICE to spread to different species of bacteria through horizontal gene transfer is a major factor in bacterial evolution. Bioinformatics approaches have been increasingly used to identify possible ICEs through sequence similarity. In this project, we aim to find out the effectiveness of using an algorithm, DLIGHT (Distance Likelihood based Inference of Genes Horizontally Transferred) that was originally used to detect lateral gene transfer, to identify integrative and conjugative elements. We will achieve this by assessing DLIGHT's ability to recover already documented ICEs. We will also use DLIGHT to test certain sequences which we suspect to contain ICEs. The predictions of new ICEs will then be vetted through manual analysis and collaboration with experimentalists.
The lymph node is a meeting point for lymphocytes with antigen-presenting cells, and rapidly expands during immune responses. Lymph node structure is highly compartmentalised, and the complex internal architecture is maintained during lymph node expansion. Therefore, mechanisms must exist to balance lymph node integrity with the need to remodel very rapidly. Fibroblastic reticular cells (FRCs) are the most abundant lymphoid stromal cell population, and span the full volume of the tissue. They provide structural support and are highly contractile. FRCs ensheathes bundles of extracellular matrix, termed the conduit, which filters draining lymph. The Acton lab works to understand how lymph nodes are remodeled during expansion and has shown that interaction between FRCs and dendritic cells change FRC behaviour. This project asks how the microtubule networks within FRCs are reorganised as the FRC network expands. Phosphoproteomic screening has revealed that LL5-beta, a protein targetting microtubules to adhesion sites is regulated by interactions between FRCs and dendritic cells. This may provide a mechanism by which FRCs uncouple from underlying matrix, and target secretion of proteases or new matrix to the expanding network. This project will investigate whether LL5-beta coordinates organization of microtubules in FRCs and whether dendritic cell contact changes LL5-beta activity.
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.
The main goal of this project is to study the allosteric regulation of Histone deacetylase 8 (HDAC8). HDAC8 is an enzyme involved in transcriptional regulation and diseases such as acute myeloid leukaemia. Recent work in the group has shown that there are changes in chemical shifts in the helix 1, loop 1 and helix 2 region of HDAC8 when the inhibitor TSA binds to the active site – chemical shift changes are observed over 28 Å from the inhibitor binding site. This is of particular interest as recent work by J. Schwabe's group has shown that this region binds co-repressors in other class 1 HDACs modulating their activity. This suggests that the information transfer between the active site and the region around helix 1, loop 1 and helix 2 is a general allosteric pathway in class 1 HDACs and is important for their regulation. In order to derive a mechanism for the allosteric regulation we will use side-chains as probes in NMR experiments. In conjunction with this we hope to characterise the transition between the drug-bound structure and the apo HDAC8 using meta-dynamics. In doing so we hope to identify key motions and residues, which mediate this transfer of information.
Chronic pain affects a large number of patients worldwide but the available treatment options are often far from adequate. The voltage-gated sodium channel Nav1.7 has been identified as a target for drugs to treat nociceptive chronic pain, but as yet no clinical candidates have been identified. Protoxin-II is a small protein found in the venom of the Peruvian green velvet tarantula, and is a potent and specific inhibitor of Nav1.7; it is therefore a promising lead as a drug for chronic pain. However, many crucial aspects of the interaction of Protoxin-II with Nav1.7 remain unknown: it is not known where the toxin binds to Nav1.7 and how this binding mode effects inhibition of the channel, or how Protoxin-II is able to select for Nav1.7 over other voltage-gated sodium channels. This project will attempt to develop an efficient and versatile synthetic route to Protoxin-II and analogues, and to use these analogues to test the structure-function relationship in Protoxin-II. This information will be used to probe its method and site of action against Nav1.7, and to design ‘toxin-drug conjugates’, analogous with antibody-drug conjugates used as treatments for cancer, with high therapeutic potential.