- Total grants
- Total funders
- Total recipients
- Earliest award date
- 14 Dec 2005
- Latest award date
- 30 Sep 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Nicotinic acetylcholine receptors (nAChRs) are major excitatory neurotransmitters and have been implicated in a number of neurological and psychiatric disorders. The primary aim of the project will be to combine synthetic organic chemistry and pharmacological techniques to examine allosteric modulation of nAChRs. This will build upon recent work in the Sheppard and Millar labs at UCL and will also exploit a refined homology model of the a7 nAChR that was generated as part of a rotation project during the first year of this PhD studentship. It is anticipated that the generation of novel compounds, combined with computer docking studies and molecular pharmacological techniques, will enable a greater insight to be gained into the mechanism of action of nAChR allosteric modulators.
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).
This application follows an invitation from Wellcome staff to apply for a small grant to support costs relating to the development of our shortlisted outline application for the Hub award Created Out of Mind: Changing perceptions of dementia through art and culture. The proposed costs will be used to cover project management of our bid, art design and branding input from creative members of our hub bid team, and travel expenses relating to a series of meetings and workshops designed to build relationships, develop conversations and discuss key questions and proposed projects within and between existing and new team members.
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.
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.
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.
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 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.
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.
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.
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.
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 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.
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.
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.
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.
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.
Positron emission tomography (PET) has become an invaluable tool for diagnostic imaging and medical research as it allows quantification of biochemical processes in vivo with unsurpassed sensitivity and specificity. Due to its near ideal physicochemical properties fluorine-18 is the radioisotope of choice for imaging applications with PET, yet the lack of efficient and practical methods for the incorporation of 18F limits the availability of clinically relevant radiotracers. In particular, late stage labelling of compounds bearing functional groups that are prerequisite to biological activity remains challenging. The Arstad group have recently developed a new radiochemical strategy for aromatic labelling of drug-like small molecules based on the unique reactivity of sulfonium salts with fluoride-18. In this project, we aim to investigate the structural requirements for labelling with 18F and to broaden the scope of the existing method by establishing complimentary synthetic routes. To demonstrate clinicalapplicability, the strategy will be used to simplify radiosyntheses of existing radiotracers, to improve the imaging properties of established tracers, and to develop novel diagnostic imaging agents. The work has the potential to open up new prospects for imaging applications with PET. Ultimately, the development of new diagnostic agents can lead to improved human health.
Public Engagement Provision 03 Dec 2014
The James Lind Alliance recently identified their 'Top 10' research prioritiesaccording to what stroke patients and their carers want. Cognitive therapies, long-term consequences of stroke and aphasia therapy were the top three priorities. My proposal will address all of these. Stroke patients with anomia and their families will be therefore be the main public beneficiaries of knowledge arising from this research. The results will inform them about brain and language recovery after stroke and potential new treatments that will directly improve their communication and quality of life.
A Two-day Conference on the Human Right to Health, Universal Health Coverage and Priority Setting. 27 Oct 2014
This grant would be used to fund a two-day conference exploring the various tensions between what the UN refers to as the progressive realisation of the human right to health, the international effort to secure universal health coverage and the inevitable need to set priorities between different treatments and services. The conference would bring together three research centres within UCL (the Institute of Global Health, the Institute of Global Governance and the Centre for Philosophy, Justi ce and Health) to hear new evidence from researchers, policy-makers and practitioners from both the UK and abroad. The conference would: i) explore existing policy drives towards HRH, universal health coverage and priority setting activities; ii) reflect upon conceptual and ethical tensions between such policies; and iii) assess the feasibility of solutions aimed at resolving this tension. The conference's main output would be a consensus statement, drawn up by Benedict Rumbold and circula ted to delegates before the meeting and discussed by attendees on Day Two of the conference itself, setting out the delegates thoughts on the next steps towards remedying the current conflict between HRH, the drive towards Universal Coverage and priority setting.