- Total grants
- Total funders
- Total recipients
- Earliest award date
- 11 Jan 2016
- Latest award date
- 06 Dec 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Background The mechanisms driving ketamine’s efficacy in treatment-resistant depression are unknown, but this treatment has been shown to elicit changes in the brain’s reward system. Together with the observation that anhedonia is specifically alleviated by ketamine, this finding has prompted the hypothesis that changes in brain and behavioural processes related to motivational processing may be important in the antidepressant action of ketamine. Main hypotheses Changes in motivational processes underlie the anti-anhedonic effect of ketamine in depression. Depressed patients experiencing a greater antidepressant response should exhibit greater neurocognitive changes in motivational processes following treatment. Research and educational goals - Method: Simultaneous fMRI+EEG imaging pre-, during, post- repeated ketamine administration and at 4 week follow-up. - Educational outcomes: Multimodal scanning, computational modelling, establishing task psychometrics. - Method: Behavioural testing in healthy and depressed individuals pre- and post- ketamine infusion combined with high-resolution fMRI. - Educational outcomes: fMRI data collection and connectivity analyses. Potential time line of proposed research Year 1 UCL: Develop behavioural tasks and neuroimaging methods; initiate tasks at the NIMH. Year 2 NIMH: Run tasks in healthy and depressed individuals during ketamine infusion and concurrent fMRI+EEG imaging. Year 3 NIMH : Retest patients at phase 3 and 4. Year 4 UCL: Neuroimaging analyses and writing thesis. Year 4 UCL: Neuroimaging analyses and writing thesis.
Cloning of a galactosyl transferase gene promoter to understand the mechanism linking genetic variation to the altered enzyme activity found in IgA nephropathy 01 Apr 2016
IgA nephropathy (IgAN) is the most common glomerulonephritis and is a major cause of kidney failure worldwide. IgAN is characterised by abnormal deposition of galactose-deficient IgA (Gd-IgA) in the kidney, and levels of Gd-IgA are raised in the serum of patients, with levels correlating with clinical outcomes [1, 2]. Why some people have elevated Gd-IgA is unknown, but we have shown that Gd-IgA levels are highly heritable [3, 4] and recently performed a genome wide association study (GWAS) that showed that the presence of a haplotype across a particular galactosyl transferase gene is strongly correlated with Gd-IgA level (p-10), implying that common genetic variation across the locus modulates enzyme activity in the population. Fine mapping of the locus using imputed genotypes, and consultation of available expression quantitative trait loci (eQTL) maps disclosed the set of common variants across the region that might explain the effect, and we now wish to understand the mechanism linking the known genetic variation with altered enzyme activity. The aim of this project is to clone the promoter region of the gene from individuals with and without the associated haplotype for studies using a reporter gene to assess promoter activity of different allotypes.
Pathophysiological consequences of mutations affecting the mitochondrial calcium uptake pathway 01 Apr 2016
Mitochondrial calcium uptake plays critical roles in cellular energy homeostasis. Alterations both in mitochondrial function and in cellular calcium signals play major roles in the pathophysiology of many major diseases, including ischaemic injury, neurodegenerative and neuromuscular diseases. The very recent discovery of the proteins mediating mitochondrial calcium uptake provides a new opportunity to understand the physiological roles of the pathway and pathological consequences of its dysfunction, as seen in patients with mutations of MICU1 described by the host lab. The patients have learning difficulties, muscle weakness and a progressive extrapyramidal motor disorder. The mechanism whereby mutations of MICU1 cause this particular constellation of symptoms are not understood. We will use iPS cells which we have generated from patient derived fibroblasts, differentiated into neurons and myotubes – the tissues most affected in the patient – and explore the consequences of MICU1 mutations for mitochondrial calcium signalling and for mitochondrial bioenergetic function. The project will illuminate the underlying mechanisms causing symptoms in the patients and point the way to therapeutic strategies.
Liposomal delivery of therapeutic agents, and/or imaging agents, is an important and rapidly emerging area which will have considerable impact on many disease areas including respiratory diseases, vaccine delivery and cancer. These liposome-based formulations are increasingly important for delivery and imaging of small molecule therapeutics, and for the delivery of plasmid DNA encoding for imaging agents or toxic genes, as they offer the benefits of cell-selective delivery with minimal off-target effects. However, to date it has not been possible to formulate both small molecule therapeutics and plasmid DNA in the same nanoparticle delivery system. The aim of this research is to develop multifunctional nanoparticles for liposomal delivery of both a small molecule therapeutic and plasmid DNA. This will have the advantage of delivering two different therapies to the same diseased cell, ensuring more rapid therapeutic effect and minimising the development of resistance to each individual therapeutic intervention.
Structural Basis of Gabapentinoid Drug Action 01 Apr 2016
Gabapentinoids are blockbuster drugs used to treat conditions including neuropathic pain and epilepsy. They act by binding alpha2delta voltage-gated Ca2+ channel subunits. The focus of this summer project is to investigate the structure of alpha2delta to help understand its role in presynaptic Ca2+ entry and reveal the molecular basis of gabapentinoid binding. We have developed constructs for alpha2delta expression in High5 insect cells and HEK293T eukaryotic cells. We will express and purify different regions of alpha2delta, taking advantage of enzymes at our disposal for modifying glycosylation and pre-protein cleavage. Co-crystallisation screens will be set up with natural and synthetic small molecules including pregabalin and gabapentin. Successful crystal hits will be tested for x-ray diffraction using an in-house x-ray source. In the final fortnight of reserach, the student will perform crosslinking coupled to mass spectrometry experiments to determine the interaction sites of different subunits within the calcium channel complex, depending on the progress of crystallisation experiments.
The Neuroscience of Nudge 01 Apr 2016
Nudges are simple behavioural methods designed to influence decision making by taking advantage of people’s implicit biases. One important type of nudge is known as "anchoring." The simple presentation of an irrelevant number affects people’s decisions by shifting estimations towards that number. This behavioural effect is well understood although the mechanism behind the unconscious bias remains unclear. The brain bases of this effect has received surprisingly little attention in the literature. One study found that the medial prefrontal cortex played a crucial role in anchoring theory-of-mind decisions in a social context, suggesting that activity within cortical networks intrinsic to the task is shaped by this extrinsic information. I propose to initiate this investigation by piloting an fMRI experiment to investigate the neural correlates of anchoring in reasoning about uncertainty. The aim is to collect a preliminary data set from a small sample of healthy adults (n=12) to explore whether the experimental paradigm: yields robust behavioural anchoring effects, identifies brain regions whose activity is affected by these anchoring effects, and tests whether these effects are parametric modulated. I predict that within prefrontal regions engaged by the task, I will observe parametric modulation based on the amplitude of the behavioural anchoring effect.
This project will involve investigating the effects of intracellular sodium on the gene expression in Dorsal root ganglion neurons. The key aims of the project will be to determine the role of sodium mediated signalling in neuronal gene expression. To determine this, high affinity sodium binding protein will be investigated; a cloned DNA construct of the protein will be transfected in to HEK (Human Embryonic Kidney) cells and then DRG neurons with a Nav1.7 knock out. The effect of low intracellular sodium concentration on expression of Penk will be assesed by analysis of the DRG neurons.
The research project represents an initial investigation into the role of the diverse components of the ventral hippocampal circuitry in the context of social interaction. The aim is to explore a potential correlation between complex behavioural patterns observed during social interaction tasks and degree of activation of ventral hippocampal neurons. Behavioural assessment will only be carried out on single housed male mice to avoid sex-specific differences. During my experiments I will compare two contexts. First, as a control, mice will be placed in a test chamber with a novel object. Second, social interaction will be tested by introducing a juvenile male. The behavioural patterns generated will be scored and compared both qualitatively and quantitatively. After 90 minutes, the degree of activation of distinct ventral hippocampal areas (CA1, CA2, CA3, Dentate Gyrus and Subiculum) will be tested in each of these groups of mice using expression of the immediate-early gene c-fos (which is correlated to neuronal activation), by optimising immunohistochemical detection in the lab. I will then aim to establish the involvement of the ventral hippocampus in social interaction by using fluorescent microscopy analysis, followed by appropriate statistical testing between the control and social groups.
We will investigate how a newly discovered mutation to the GABA-A receptor alpha 1 subunit gene (GABRA1) is causing epilepsy in a young child. A single mutation has been identified, which resides in the receptor's first transmembrane domain. This is near the previously identifed neurosteroid binding site from which endogenous neurosteroids can positively modulate GABA-A receptor activity. To investigate the implications of this mutation we have formulated the following aims that will be addressed using heterologous expression of GABA-A receptors in a cell line: 1. To establish the effect of the mutation on GABA concentration response curves and current voltage relationships for typical synaptic and extrasynaptic-type GABA receptors. 2. To determine if known allosteric modulators of GABA-A receptors are affected by the alpha1 subunit mutation. 3. To deduce if the expression levels and receptor mobility at the cell surface are affected by the alpha 1 subunit mutation. To achieve these goals, we will use a combination of patch clamp electrophysiology and single particle imaging techniques. This should establish whether the mutation is causing a gain- or loss-of function, or affects receptor trafficking.
Ultrasound at high intensities can cause tissue damage, therefore knowing the intensities used in clinical application is paramount. Ultrasound source outputs are calibrated using hydrophones, following a primary standard calibration at the National Physical Laboratory (NPL) in the UK. Yet uncertainty in the primary calibrations is surprisingly high: around 10% and growing with frequency (NPL 2014). The primary calibration uses optical interferometry for the measurements. This project will investigate one source of uncertainty in this procedure: the effect of the tension in the optically-reflecting membrane. The rig for these experiments will be designed and built following the design shown in Figure (1). There are three key goals: a) Create a measurement rig that can measure the normal incidence acoustic pressure transmission coefficient of a stretched mylar membrane as a function of frequency, membrane tension, and membrane thickness. b) Based on previous work in the literature (Thomas 1976; Romilly 1969; Lamb 1957; Ingard 1954; Chen et al. 2014), construct a mathematical and/or numerical model of the motion of a membrane under tension when a sound wave is incident, and make for comparison with the measurements. c) Formulate advice to the National Physical Laboratory on how to minimize this uncertainty.
The goal of the project is to express the reverse transcriptase (RT), central to the Bordertella phage BPP-1 diversity generating retroelement (DGR), and test it for synthetic nucleic acid (XNA) synthesis as well as reverse transcription. In addition, I will focus on cloning the BPP-1 DGR elements into E. coli, creating a circuit where DGR function can activate a selectable marker (e.g. kanR). I will try and demonstrate that the BPP-1 DGR is active in E. coli and can be used as a tool for in vivo directed evolution.
Investigating the neural odometer function of entorhinal grid cells in rats navigating a multi-planar environment. 01 Apr 2016
It has been proposed that the grid cell system in the medial entorhinal cortex acts as a ‘neural odometer’, encoding both distance travelled and an animal's position in space. These features may be necessary for spatial computations such as path integration, but the relationship of grid cell firing patterns to behaviour remains speculative. In not-yet-published work, it has been shown that for a rat climbing a wall with its body plane aligned vertically the grid fields are expanded, as if the cells underestimate distance travelled. If grid cells support spatial computations then rats should also underestimate distances in this plane. To test this hypothesis rats will learn a distance match-to-sample task leading to triangle completion while both sample and choice phases are in the same plane (both horizontal or both vertical). In probe trials, the sample will be horizontal but the choice vertical. Distance underestimation in the probe trials (walking too far on the vertical wall to achieve a match to the horizontal sample) will link grid cells to behaviour, while the basic distance-matching task will serve as a springboard for neurobiological studies investigating the role of grid cells in odometry generally.
The key goal of my research is to determine whether a new Electrical Impedance Tomography system which has been developed at UCL, is suitable for use in imaging stroke patients. This system would provide a fast, safe, and inexpensive method of distinguishing between strokes resulting from cerebral ischaemia and haemorrhage. If the different types of stroke could be distinguished on site by paramedics it would enable treatment and 'clot busting' drugs to be administered immediately, increasing patient survival significantly. I will be conducting the final clinical studies of this system, on patients who are admitted to the Acute Admissions Unit at UCH. I will identify suitable patients who have suffered a stroke and, with consent, take readings using the new EIT system. The images produced will be optimised using newly developed techniques, and compared to MRI and CT images. After the main bulk of data collection, the rest of my project will involve refining the accuracy of the instrumentation, including calibration, assessment, and reduction of electrode noise. I will then analyse the data produced, using Matlab, and evaluate whether the new EIT system is suitable for use in clinical applications.
As we perceive the world, our brain continuously makes educated guesses about what we will see next. These inferences allow us to distinguish objects in our field of vision without having to examine every detail. This is known as the Bayesian model of visual perception. Recent evidence suggests that object recognition tasks for which such inferences are likely to be crucial may develop well into adolescence. There is anecdotal evidence that children find tasks such as identifying objects in poor lighting conditions or when borders are unclear (Bova, 2007) very difficult, even when they know exactly what the object they are looking for looks like (Yoon, 2007). This suggests that the robust object perception described in Bayesian models of the adult system takes surprisingly long to develop. This piece of research will test this hypothesis by (a) measuring children’s ability to recognize objects in a distorted ("noisy") image, and (b) testing how expectations about the objects (e.g. what it will look like) can improve perception. This aims to further our understanding of how the brain learns to use existing knowledge to interpret new sensory information, and make better inferences about the world.
Loss of GABAergic cells and night-time hyperactivity in zebrafish mutants of autism risk genes 01 Apr 2016
Night-time hyperactivity makes up part of the unique behavioural profile of autism spectrum disorder (ASDs). Recent studies on zebrafish revealed that loss-of-function mutations in autism risk genes (e.g. CNTNAP2) lead to a reduction in GABAergic neurons in the hypothalamus. GABAergic cells are sleep promoting and play an important role in the regulation of sleep-wake cycle. There are different subtypes of GABAergic cells, such as galanin-positive and MCH-positive neurons. In this project, we are going to investigate what subtypes of GABAergic cells are lost in autism mutants, using in situ hybridisation and basic microscopy. Significant difference in the amount of cells present in the wild-type and mutant will be expected.
Development of a novel bioartificial liver device for the treatment of patients with liver failure 30 Sep 2016
In the UK, over 16,000 patients a year die of liver failure. Their livers have the capacity to repair and regenerate, but do not have time to do so. A device temporarily replacing liver function would save lives and reduce the necessity for liver transplantation worldwide. Dr Clare Selden and her team at UCL have developed a prototype 'bio-artificial liver' (BAL) to address this unmet need. Its key element comprises functioning liver cells in an external bioreactor. Plasma from a patient with liver failure will be passed through the bioreactor, contacting the alginate encapsulated liver cells, so that the cells replace those functions that the sick liver cannot perform. The machine will buy time for a patient's liver to improve or, if damage to the liver is irreversible, may buy time until liver transplantation can be arranged. The technology combines alginate encapsulation of a human liver cell line and subsequent culture of the encapsulated cells in a fluidised bed bioreactor - providing a convenient, manipulatable biomass in a form which maximises mass transfer between cells and perfusing plasma. The team have Translation Award funding to complete the design, specification, performance characterisation and manufacture of this fully biocompatible BAL.
A computer assisted system to reduce auditory hallucinations unresponsive to antipsychotic medication 30 Sep 2016
About 25% of people with schizophrenia continue to suffer with persecutory auditory hallucinations despite drug treatment. Their capacity to work and make relationships is grossly impaired, often for the rest of their life. Professor Julian Leff from University College London and colleagues at Speech, Hearing and Phonetics, UCL have developed and evaluated a novel therapy based on computer technology which enables each patient to create an avatar of the entity (human or non-human) that they believe is talking to them. The therapist promotes a dialogue between the patient and the avatar in which the avatar progressively comes under the patient's control. This translation award aims to refine the system, streamline the technology to make it more user-friendly and evaluate the system by a randomised controlled trial conducted by an independent team of researchers at the Institute of Psychiatry, King's College London.
A phase I clinical trial of DARC 30 Sep 2016
Preclinical development of a novel diagnostic for glaucoma. Glaucoma is the major cause (15 per cent) of irreversible blindness worldwide. A recent UK report suggested 10 per cent earlier detection of glaucoma would save £1billion/year in treatment costs alone.Professor Francesca Cordeiro and colleagues from the Institute of Ophthalmology at University College London, have been given Translation Award support to fund the preclinical development of their Detection of Apoptosing Retinal Cells (DARC) Technology. DARC is a novel technique that utilises the unique optical properties of the eye to allow direct visualisation of dying nerve cells. If successful, early diagnosis and treatment would mean that DARC will increase patient benefit and decrease burden of care costs.
Little is known about the longitudinal effects of child soldiering onto the lives of these participants in wars, particularly in the children’s transition to adulthood. A culturally-grounded understanding of the multiple levels in which this experience shapes their subsequent lives in highly politicised communities is needed. My aim is to conduct a pilot assessing the feasibility of a future study on the long-term effects of early age involvement in political violence in the context of Nepal. This pilot will lay the foundation for a future application of funding for a larger research project. Knowledge of these effects will inform policy-makers and the rehabilitation services’ ability to support this population into adulthood. The funding will enable the facilitating of: i) A pilot in Nepal where I will reengage with my former PhD cohort of informants; ii) Workshops in Nepal and the UK to discuss the results of the pilots with scholars, informants, and stakeholders; iii) Time to prepare an academic paper. The key outputs will be: i) an assessment of the feasibility of the study; ii) the development of a network of collaborators; iii) an academic paper drafted for an academic journal. Key words: child soldiers, ethnopsychology, longitudinal research, war.
A cross-cohort comparison of unhealthily low BMI in early adolescence – a feasibility study and development of research protocol 31 Jan 2016
Childhood thinness (unhealthily low body mass index) has been linked to poorer health and development but has received relatively little research attention in high income countries. Contemporary routine data reported by the National Child Measurement Programme (NCMP) point towards a possible U-shaped socio-economic gradient in thinness in 10-11 year olds (whereby those living in the most and least deprived areas have elevated rates of thinness). However, since the main focus of the NCMP is overweight and obesity, this social patterning in thinness has not been emphasised or further investigated. The U-shaped socio-economic distribution in thinness may be explained by food poverty in more disadvantaged areas, and issues of body image and eating disorders in more advantaged groups. UK cohort studies provide an untapped resource for examining this issue, because they contain rich, individual-level data, spanning different time periods (exposed to different social and economic contexts). However cross-cohort comparisons can be challenging and require a lot of input at the planning stage. This proposal therefore comprises of a feasibility study for a cross-cohort investigation of individual-level socio-economic inequalities in thinness in young people (and possible reasons behind them).