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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Recipients:
University College London
Amounts:
£500 - £1,000

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Results

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.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Combined liposomal delivery of small molecule and oligonucleotide therapeutics 01 Apr 2016

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.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

The motivational mechanisms driving the antidepressant effects of ketamine 25 Jan 2016

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.

Amount: £80,000
Funder: The Wellcome Trust
Recipient: University College London

AMARI: African Mental Health Research Initiative 05 May 2015

Mental, neurological and substance use (MNS) disorders are a leading, but neglected, cause of morbidity and mortality in sub-Saharan Africa [1]. MNS disorders account for >25% of all years lived with disability globally, more than cardiac disease or cancer [2]. The treatment gap is vast, only 10% of people with MNS disorders in low-income countries access evidence-based treatments, compared to 33% in high-income countries [3]. Reasons for this include low awareness ofthe burden of MNS disorders and limited evidence to support development, adaptation and implementation of effective and feasible treatments. While pockets of mental health research excellence exist in Africa, MNS research capacity is generally limited, particularly in mental health intervention, service and system research. Mental health research excellence is currently undermined by restricted opportunities for training and mentorship, unclear career pathways, lack of integration in general medical settings, limited multi-disciplinary collaboration and the lack of a critical mass of MNS researchers and leaders. The overall goals of the African Mental Health Research Initiative (AMARI) areto build an African-led network of MNS researchers in Ethiopia, Malawi, South Africa and Zimbabwe, equipped to lead high quality mental health research programmes that meet the needs of their countries, and to establish a sustainable career pipeline for these researchers with the emphasis on integrating MNS research into existing programmes such as HIV/AIDS, maternal and child health. The objectives are to: 1. Select and train MNS research fellows from a range of disciplines at masters (n=25), PhD (n=20) and post-doctoral (n=6) levels in research excellence; 2. Build leadership skills of 26 fellows through adaptation of KCL Career Development Series on Leadership, Management and Mentoring; 3. Design and test an advocacy and systems change strategy for each country, aimed at building sustainable career pathways in MNS academia; 4. Develop a web-based support platform for training, supervision and networking. In year 1 we will undertake preparatory work to inform course development, thedesign of the advocacy and systems change strategy and gather baseline data for each country, for evaluation purposes, conducting qualitative and quantitative interviews with local policymakers and service users to identify needs and priorities through a theory of change map. We willtrain local supervisors, run pre-application workshops for potential applicants and assess existing training materials. . In years 2-5, fellows will begin higher degrees and courses as relevant. Trainingwill be mostly in Africa and using a) joint supervision by local and external supervisors with multidisciplinary expertise, b) taught modules in advanced MNS research methods, writing, and engagement with policy makers, and c) undertaking high priority MNS research. The underlying ethos of AMARI will be to ensure LMIC partner capacity is strengthened progressively towards self-sufficiency to ensure sustainability longer term. AMARI will be led by University of Zimbabwe College of Health Sciences (UZ-CHS). All consortium institutions will provide course facilitators and supervisors, with the Centrefor Global Mental Health (CGMH), University of Cape Town (UCT) and University College London (UCL) providing external supervision, research experts and materials for adaptation.

Amount: £49,068
Funder: The Wellcome Trust
Recipient: University College London

Molecular makeup of astroglia probed with super-resolution microscopy. 09 Feb 2015

In our quest to decipher the brain circuit machinery astroglia have emerged as an important third participant of the signal exchange between pre- and postsynaptic neurons. To understand principles of information processing in such tripartite circuits represents a conceptual challenge. How the multiple modalities of intracellular astrocyte signalling translate into meaningful communication with neurons remains poorly understood. Our long-term aim is therefore to understand how generation, propagation and storage of informative signals in tripartite brain circuits form memories and shape a physiological response, in health and disease. We will take full advantage of the on-going methodological revolution in sub-cellular real-time imaging, coupled with pharmaco- and optogenetic approaches ex-vivo and in-vivo and aided by biophysical and neural-network modelling. The five-year strategy will build upon our recent discoveries which have unveiled novel principles of synaptic organisation and plasticity including the regulatory role of astrocytic signalling. Firstly, we will employ our novel FLIM-based Ca2+ imaging technique to decipher the code of causalitiesarising between the synaptic identity and Ca2+ homeostasis machineries at tripartite connections. Secondly, we will establish how the diverse neural signals are integrated and possibly stored by non-excitable astroglia operating their Ca2+-wave communication medium.Thirdly, we will explore and expand the classical rules of synaptic plasticity to meta-plasticity of the tripartite synapse. Fourthly, we will establish how the operational assemblies of nerve and glial cells interact to support a physiological function. Finally, we will attempt to formulate how astroglial signalling impinges on functional modalities of theoretical neural networks.

Amount: £149,352
Funder: The Wellcome Trust
Recipient: University College London

Structural biology of protein folding on the ribosome: exploring mechanisms biochemically and computationally. 08 Dec 2014

We are delineating the very early dynamic structural events of protein synthesis as they occur on the ribosome. Despite the abundance of ribosome structures, the structural properties of the emerging nascent polypeptide chain (NC) are almost entirely absent. We apply NMR spectroscopy to the 2.5MDa ribosomal particle, as it has the unique ability to describe the structural and dynamical characteristics of fledgling NCs emerging during biosynthesis.

Amount: £130,000
Funder: The Wellcome Trust
Recipient: University College London

Defining the role of NRP1-ABL1 signalling in adult neovascular eye disease 02 Oct 2014

We wish to address if ECM-induced NRP1-ABL1 signalling promotes adult angiogenesis and is a suitable target in anti-angiogenic therapies. In both PDR and wet AMD, VEGF is upregulated and stimulates angiogenesis to counter tissue hypoxia caused by vascular damage. Whereas neovascular lesions in PDR affect intraretinal vessels and resemble those in retinopathy of prematurity, wet AMD is instead caused by abnormal choroidal vessel growth. In addition to causing vascular abnormalities, high ocular VEGF levels are associated with vascular fluid leak, which causes oedema and impairs vision in both conditions. Because anti-VEGF therapies such as Lucentis® and Avastin® efficiently target vascular hyperpermeability, they are the approved treatmentfor oedema in PDR and AMD. They stabilise sight in over 90% of AMD patients, however, only 30% show improved vision (2), demonstrating that these therapiesare not sufficient for all patients. Recent evidence also suggests that anti-VEGF therapy is not curative, because neovascular lesions persist and oedema returns as soon as treatment is discontinued (3). Our prior research predicts that one reason for the persistence of neovascular lesions may be thefailure of anti-VEGF therapy to target ECM-induced angiogenesis via NRP1-ABL1 (Fig. 1). Furthermore, a multicentre cohort clinical study showed that, after seven years of treatment with anti-VEGF therapies, only one third of patients had good visual outcome and another third had poor outcome (4), with loss of protective VEGF functions in the neural retina likely contributing to retinal atrophy (5, 6). Thus, new treatments for neovascular eye disease should not compromise neuroprotection. Our discovery of an angiogenic NRP1/ABL1 pathway that can be targeted with the FDA-approved drug Imatinib independently of VEGFmay therefore provide a timely new therapeutic opportunity for neovascular disease.

Amount: £66,200
Funder: The Wellcome Trust
Recipient: University College London

Topical delivery of Ranibizumab for non-invasive treatment of retinal disease 16 Apr 2015

Age-related macular degeneration (AMD) is a major cause of blindness, affecting 30- 50 million people worldwide, with a rising incidence due to the rapidly increasing aging population. Current treatments, of which Ranibizumab is the most frequently prescribed, involve monthly injections into the eye to block a protein known as VEGF (vascular endothelial growth factor), responsible for new blood vessel formation. However, at £85 million/year in the UK, injections carry a high burden to the health system, requiring specialist-clinic administration. There is a clear, unmet need for anti-VEGF treatments therefore to be non-invasive, easy to administer and less expensive. Professor M Francesca Cordeiro and her team at UCL have developed a formulation that can be used to replace monthly hospital-administered intraocular anti-VEGF injections with daily self-administered eye-drops. This project aims to optimize the formulation for Ranibizumab, develop its manufacturing process, and assess its safety and tolerability to enable it to be tested in First-in-Man clinical trials. If successful, the Ranibizumab eye-drop will lead to widespread treatment programmes - potentially reducing the burden of AMD on the individual and society by changing the way treatment is delivered within five to seven years.

Amount: £1,666,193
Funder: The Wellcome Trust
Recipient: University College London

Image-guided neurosurgical treatment of epilepsy 16 Apr 2015

One third of individuals developing epilepsy are uncontrolled with medication. If epilepsy arises from one part of the brain, surgical removal of this area can be curative. This needs to be balanced by the risk of causing new deficits such as paralysis or impaired speech. Improved diagnostic methods, and surgical precision, will improve the benefit/risk ratio of epilepsy surgery, and increase treatment availability. At University College London, teams led by Professor John Duncan and Professor Sebastien Ourselin have developed software to visualise the whole range of 3D brain imaging, including normal architecture, abnormalities of structure and function, arteries, veins, critical brain areas and nerve pathways, and the skull. This increases the safety and precision of implantation of the electrodes necessary to pinpoint the brain tissue that needs to be removed to cure the epilepsy. This project aims to implement automated planning of electrode trajectories and robotic systems for placing the electrodes into the brain. It will also establish methods for automated 3D planning of neurosurgical resections, so that surgery is optimal and quicker. Consequently, curative neurosurgery will be available more quickly to more individuals. The surgical advances pioneered here will be applicable in future to other procedures, such as taking biopsies and tumour surgery.Note this is a HICF award but funded solely by the Trust as a Translation Fund project

Amount: £1,757,340
Funder: The Wellcome Trust
Recipient: University College London

Smart laparoscopic liver resection: integrated image guidance and tissue discrimination 30 Sep 2015

Liver cancers can be removed using key-hole surgery with less pain, tissue damage, and blood loss and faster recovery times than traditional open surgery. However few cancers are removed by this method because of the difficulty in identifying and dividing blood vessels within the liver using key-hole surgery techniques. In addition, the position of the tumour and major vessels in the liver alters during the surgery due to patient breathing and liver traction. A research group headed by Professor Brian Davidson and Professor David Hawkes at University College London proposes to use the CT scan taken prior to surgery to identify the precise location of the cancer to the surrounding vessels and bile ducts and hence build a computer model of the liver for each individual patient. They will use this to monitor the position of the cancer and the major structures to the liver during the course of the key-hole surgery. This will be combined with a new method of detecting what kind of tissue is directly in front of the cutting instrument. This system is likely to result in a significant increase in the proportion of patients who undergo liver resection using key-hole surgery. The system will be validated on pigs and then evaluated on at least 25 patients. The system developed will also be applicable to operations on the pancreas, kidney and gallbladder.

Amount: £211,297
Funder: The Wellcome Trust
Recipient: University College London

Institutional Strategic Support Fund Phase2 FY2014/16 27 Oct 2014

We were successful in renewing our WTISSF, which provides £3million over the next two years and will cover five key areas: Investment in excellent researchers Investment in infrastructure Translational research Cross and interdisciplinary research Public engagement. The remit of the renewal is more focussed than it was previously. It now concentrates on supporting activities that align with the strategic priorities of the UCL School of Life and Medical Sciences (SLMS) and the four faculties. The next call will be seeking applications in the following three areas, with approximately £800,000 of WTISSF funding available: 1) Neuroscience - funding can be requested to support the following activities: Planned staff recruitment; contribution to the recruitment of senior staff, or exceptionally bridging funds for key personnel. Please note that for bridging funds it is essential to detail the added value of the bridging funds and how the post funded will be supported in the future. Planned equipment purchase of specific items of equipment, or a contribution to the cost. Collaborative interdisciplinary projects and networking activities; funding to support new collaborative research projects or networking activities. 2) Informatics - funding can be requested to support the following activity: Planned staff recruitment; to develop capacity in people (researchers or technical staff) with expertise in computational biology, health informatics, large datasets or developing new analytical techniques. 3) Imaging - funding can be requested to take advantage of our capital investment in imaging to develop these technologies: Pump-priming research projects. Planned recruitment of technical support staff.

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: University College London

The population impact of delirium on long-term cognitive impairment. 17 Jun 2015

Delirium is one of the most common complications of acute illness in older adults yet it remains poorly understood. This fellowship will investigate prospectively population delirium incidence with cognitive outcomes. In parallel, I will test new methods for informatics-based delirium ascertainment for use in longitudinal studies. Hypothesis: Incident delirium is associated with changes in global cognitive scores (pre-delirium compared to scores at two-year follow-up). Methods I will recr uit a population-based cohort of 2,000 individuals aged 65 years and older. Participants will undergo baseline cognitive assessments. Then, participants will be proactively monitored for episodes of delirium, via: (i) telephone contact of highest-risk participants/informants (ii) daily screen of hospital admissions lists. Hospitalised participants will be assessed for delirium and associated clinical data. I will continue to assess cognitive function after discharge (four-monthly), with a whole- cohort assessment at 2 years. Reference-standard delirium diagnoses will be used to develop and validate algorithms for delirium ascertainment from electronic health records. Outcomes This study will be the first prospective population cohort relating delirium and its features to risk of long-term cognitive impairment. Validated informatics-based delirium measures will allow wide exploitation of clinically rich datasets for the enhancement of other prospective studies.

Amount: £955,416
Funder: The Wellcome Trust
Recipient: University College London

Wellcome Beit Prize 2014/2015- The population impact of delirium on long-term cognitive impairment. 17 Jun 2015

Delirium is one of the most common complications of acute illness in older adults yet it remains poorly understood. This fellowship will investigate prospectively population delirium incidence with cognitive outcomes. In parallel, I will test new methods for informatics-based delirium ascertainment for use in longitudinal studies. Hypothesis: Incident delirium is associated with changes in global cognitive scores (pre-delirium compared to scores at two-year follow-up). Methods I will recr uit a population-based cohort of 2,000 individuals aged 65 years and older. Participants will undergo baseline cognitive assessments. Then, participants will be proactively monitored for episodes of delirium, via: (i) telephone contact of highest-risk participants/informants (ii) daily screen of hospital admissions lists. Hospitalised participants will be assessed for delirium and associated clinical data. I will continue to assess cognitive function after discharge (four-monthly), with a whole- cohort assessment at 2 years. Reference-standard delirium diagnoses will be used to develop and validate algorithms for delirium ascertainment from electronic health records. Outcomes This study will be the first prospective population cohort relating delirium and its features to risk of long-term cognitive impairment. Validated informatics-based delirium measures will allow wide exploitation of clinically rich datasets for the enhancement of other prospective studies

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University College London

Medicine Corner - costed extension 20 Apr 2015

This extension funding will cover the engagement by SNEHA of two consultants. One will assist with Dharavi Biennale activities as the project winds down. Both will work on Medicine Corner, the Wellcome Collection's programme of cultural activity exploring Indian medicine, health and wellbeing.

Amount: £6,300
Funder: The Wellcome Trust
Recipient: University College London

Chronic Disease in Sub-Saharan Africa: a critical history of an 'epidemiological transition'. 20 Jan 2015

According to the WHO, Africa is the latest region of the world to be on the cusp of an epidemic of chronic disease, with rising rates of mortality and morbidity from cardiovascular disease, stroke, diabetes, chronic hepatic and renal diseases as well as cancer, mental illness and HIV/AIDS (now widely viewed as a chronic condition). It is projected that by 2015, a quarter of all deaths on the African continent will be caused by such diseases and their concurrence with infectious diseases. High-le vel meetings have produced a plethora of policy documents directed at the very significant challenges that this apparent epidemiological shift poses for already fragile health systems on the continent. A variant of modernisation theory, the historical framework of the epidemiological transition has been widely criticised, but its broad parameters remain at the heart of current policy-making. Accumulating evidence from different regions of Africa, as well as comparative work on India, China, Lati n America and the historical experience of Europe, suggest that this linear model of change may need more radical re-thinking. Recognising the real importance of these issues, this project has two central goals. Firstly, it will take a step back and ask some critical questions about the definitions and measurements of 'chronic' and 'non-communicable' diseases and examine the evidence for their longer history in sub-Saharan Africa. Secondly, through a set of case studies it will provide much-need ed in-depth research on the current situation in sub-Saharan Africa, paying particular attention to 'co-morbidities'.

Amount: £997,498
Funder: The Wellcome Trust
Recipient: University College London

The molecular basis of islet amyloid induced beta-cell death and the inhibition of islet amyloid induced toxicity 07 Jul 2015

Amyloid formation plays a central role in a wide range of devastating diseases, but the mechanism of amyloid formation has yet to be defined in detail for any protein. The nature of the toxic species produced during amyloid formation is controversial and efforts at drug development have been disappointing. This proposal exploits new approaches, developed in our laboratory, to address these critical issues. Our work is focused on islet amyloidosis by the neuropancreatic hormone islet amyloid polypeptide (IAPP, also known as Amylin) and its role in type-2 diabetes (T2D) and beta cell death. Key questions are: (1) What is the mechanism of IAPP amyloid formation?(2) What are the properties of the toxic oligomers produced during islet amyloidosis? (3) What distinguishes toxic from non-toxic oligomers and what factors correlate with toxicity? (4) Why do some amyloid inhibitors protect against toxicity while other promote it? Answering these questions is central to an understanding of amyloidosis and to developing effective therapeutic strategies.

Amount: £1,732,599
Funder: The Wellcome Trust
Recipient: University College London