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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

THE PHYSIOLOGICAL ROLE OF CLATHRIN LIGHT CHAIN DIVERSITY IN VERTEBRATES. 07 Jul 2015

Clathrin-coated vesicles (CCVs) influence cell-cell interaction for all eukaryotic organisms by mediating membrane traffic pathways that control receptor expression and organelle formation. The biochemistry of how clathrin polymerizes into a lattice to form a CCV is understood at a basic level, but how CCVs meet the transport challenges posed by specialized cargo and membrane variation in different vertebrate tissues is not fully defined. It is known that adaptor molecules incorporated into the clathrin coat are variable and have variable cargo specificity. However, recent studies suggest a new paradigm in which properties of the clathrin lattice itself, conferred by the light chain subunits, also influence coat selection of cargo. Although identified as obligate clathrin subunits 35 years ago, the functions of the clathrin light chains (CLCs), which display tissue-specific isoform variation, are not fully established. The emerging role for CLCs in a novel coat function and their ti ssue variability beg the overall question addressed here: How does the CLC component of the clathrin coat affect cargo transport and influence the physiological function of clathrin in vertebrates? Specific questions to be addressed through protein chemistry, cell biology and mouse genetics are Question 1: How do CLC isoforms affect the biochemical properties of clathrin? Question 2: How do CLCs affect cargo specificity of CCV transport? Question 3: How does CLC variability influenc e vertebrate tissue morphology and function?

Amount: £51,200
Funder: The Wellcome Trust
Recipient: University College London

The mechanism controlling sorting and axonal retrograde transport in neurons. 01 Apr 2015

Neurons have unique morphologies, which are maintained by transport events allowing precise communication over long distances. Fast axonal transport constitutes the backbone of these trafficking pathways and is required for neuronal development and survival. Accordingly, several neurodegenerative diseases are associated with deficits in axonal transport, suggesting a causal role for axonal transport dysfunction in disease pathogenesis. Multiple evidence link fast axonal transport and neuronal homeostasis, yet the mechanisms responsible for long-term transport and sorting of physiological ligands, such as neurotrophins and their receptors, are still unclear. Our overall aim is therefore to define: What are the molecular mechanisms controlling cargo uptake and sorting along the axonal transport route? We uncover an essential role for nidogens, key components of the synaptic basement membrane, in the uptake and axonal transport of tetanus neurotoxin (TeNT), and clinical tetanus. Bas ed on our findings that TeNT exploits a trafficking route used by neurotrophins for their long-range transport and signalling, this proposal aims to uncover the role of nidogens in axonal retrograde transport and neuronal survival. Using a combination of biochemistry, cell biology and intravital imaging and taking advantage of our ability to analyse axonal transport in-vitro and in-vivo, we will address the following questions: i) Do nidogens undergo axonal retrograde transport and trans- synaptic transfer in neurons? ii) What is the nature of the receptor complex targeting nidogens to this route? iii) Which signals modulate axonal transport of nidogens? iv) What is the physiological function of nidogens undergoing axonal transport?

Amount: £1,747,223
Funder: The Wellcome Trust
Recipient: University College London

Neural and Computational Mechanisms of Categorisation. 01 Apr 2015

Judging a person as a friend or foe, a tumour as cancerous or benign, or a sound as an \l\ or \r\ are examples of categorisation tasks. Category knowledge provides a necessary basis for almost every cognitive act, ranging from assessing the value of an object to problem solving. For example, the perceived value of a shiny object will depend on whether it is categorised as a piece of glass, a synthetic diamond, or the Koh-i-Noor diamond. My research question is whether people's ability to acquire and use categories arises from interacting brain processes that sample aspects of the external (e.g., by eye movements) and internal (e.g., by memory retrieval) world. This recasting of basic constructs in attention and memory is carried by three interrelated aims: Firstly, A) how attention alters category representations in the brain will be investigated, then the mechanisms that give rise to such phenomena will be unpacked in terms of hypothesised B) external and C) internal sampling processe s. In contrast to the standard view, which holds that attention, memory, and decision involve distinct stages of processing, I propose that these functions are rooted in interacting sampling processes. My main hypothesis (see Figure 1) is that categorisation decisions are made by internally sampling from memory until sufficient evidence is accumulated to respond. During this limited-retrieval process, the probability that a memory is retrieved varies as a function of its recency and attentio n-weighted similarity to the external stimulus. These similarity relations can change within a decision as a result of external sampling (e.g., eye movements). External sampling can be strategic (i.e., guided by current beliefs and goals). The interplay of these internal and external sampling processes gives rise to attentional effects and the apparent dynamic character of human knowledge. My main hypothesis concerns sampling processes within a decision episode that shape category representa tions over time. Standard paradigms (e.g., factorial design and comparisons of conditions) are not suited to evaluating how brain state and category representations change over time because these methods fail to specify or evaluate the underlying mechanism. Instead, my team will develop cognitive models that describe how processes unfold and representations change over learning and relate these hypothesised mechanisms to multivariate patterns of neural activity in imaging studies where participa nts learn about novel categories. The integration of behavioural measures (e.g., choice, response time, eye movements), neural measures (e.g., fMRI), and cognitive modelling will provide the necessary theoretical constraints. This formal integration is made possible by the novel cognitive modelling and multivariate analyses developed in this proposal, which will help explain how the brain acquires and uses categories.

Amount: £1,099,887
Funder: The Wellcome Trust
Recipient: University College London

Supportive supervision of mid level health workers in rural Nepal for improved job satisfaction, motivation and quality of care. 25 Mar 2015

Many low-income countries are suffering from a shortage of health workers in rural areas. In response to this, tasks are being shifted to mid level cadres who are often working without adequate management and support mechanisms. These cadres require emotional and clinical support in order to develop and retain their skills, and an enabling environment to provide good quality care. The evidence base about the impact of supportive supervision on primary health care is weak, and there is a need to develop the theory about how supportive supervisions may work. We will conduct action research with central and district level stakeholders, and health workers to describe and explore the difficulties facing mid level health workers, and discuss current weaknesses in existing supervisory mechanisms. We will also explore supervision preferences of mid level health workers, and the effect of gender and difference in cadre on supervisory needs through qualitative interviews in three districts. We will critically examine pilot interventions and conduct a realist review of the national and international literature to identify potential interventions which could be implemented for mid level health workers in rural Nepal. Findings will be fed back and discussed in a working group, and interventions presented to a wider group of stakeholders at a workshop. Cost information will also be prepared and presented at this workshop. After participatory prioritisation of interventions, we will develop an evaluation methodology and theories of change, which we will present at a dissemination meeting. We will seek funding for the implementation and evaluation of the prioritised supportive supervision interventions, and identify pilot districts in which to test interventions. We will disseminate our methodology and interventions among academic and practitioner audiences.

Amount: £33,367
Funder: The Wellcome Trust
Recipient: University College London
Amount: £24,959
Funder: The Wellcome Trust
Recipient: University College London

A novel biomarker platform for dementia research with single molecule sensitivity. 11 Jun 2015

Identification of biomarkers is increasingly important in diagnosis and therapeutic decision making in most areas of medicine and particularly so in neurological conditions due to difficulties of direct visualisation and tissue sampling of the central nervous system. Biomarkers are also critically important for clinical trial inclusion criteria and as outcome measures. Sensitive methods to measure markers are constantly sought and in clinical neuroscience cerebrospinal fluid (CSF) is one of the most promising biomarker matrices, although CSF volumes are often limited and not easily resampled. Biomarkers in CSF are at low concentration and so are not easily measured. A key objective is to develop novel biomarkers for core neuropathological changes in neurological diseases using ultrasensitive Simoa technology. The equipment requested is a fully automated analyser manufactured by Quanterix , the Simoa HD-1. Simoa (single molecule array) technology is based on standard immunochemical tec hniques and uses paramagnetic beads and standard reagents but is able to achieve much greater sensitivity than standard techniques due to the ability to trap single molecules in femtolitre volume wells allowing for a digital readout. measuring at the single molecule level. This can lead to up to 1000-fold better analytical sensitivity, compared to traditional ELISA techniques.

Amount: £119,531
Funder: The Wellcome Trust
Recipient: University College London

A preclinical magnetic resonance imaging system for neurology and oncology. 11 Jun 2015

This application is for a high-field (9.4T), preclinical MRI scanner. The key objective of the proposal is to increase the capacity for preclinical MRI at UCL, in order to support a research programme focussing on excellence in neuroscience and oncology. Currently, access to preclinical MRI at the UCL Centre for Advanced Biomedical Imaging (CABI) is limited to a single scanner, which was funded in 2008 by the British Heart Foundation to develop cardiac imaging. This system is used at full cap acity and is typically booked up to three months in advance. Many requests that the Centre receives for collaborative research cannot currently be facilitated, despite their potential for scientific excellence and for generating novel, highly impacting results, or must be tailored to the constraints of the currently available infrastructure. If funded, this proposal would enable cutting-edge research projects (including research into neurodegeneration, optogenetics and non-invasive tumour his topathlogy) to be undertaken robustly and without compromise. Several of the projects outlined in this application have elements of 'blue-skies' research that are highly novel and could generate data that is impacting, important and could provide benefit across numerous disciplines.

Amount: £870,000
Funder: The Wellcome Trust
Recipient: University College London

Shared equipment application for a NIRx Near Infrared Spectrometer (NIRS) system for functional measurements (fNIRS). 11 Jun 2015

We request a Near Infrared Spectrometer (NIRS) to be shared primarily by researchers in speech, hearing and language to make functional NIRS measurements (fNIRS). NIRS is a non-invasive method that measures the absorption of near-infrared light through the intact skull. Similar to fMRI, fNIRS provides an indirect measure of neural activity based on changes in blood oxygenation due to metabolic processes within the cortex. The equipment will be used in research that involves hypotheses that can b e tested based on activations near the cortical surface where the procedures or participants make it difficult or impossible to use fMRI. It can be used with children, people with cochlear implants, and people with conditions or in experiments that make it difficult to remain stationary whilst speaking or listening. The equipment will help extend established research programmes and there are plans in place to permit junior PIs to share and develop new research in a way that will make the facilit y self-sustaining. The research falls within Wellcome Trusts vision statement to improve health.

Amount: £206,772
Funder: The Wellcome Trust
Recipient: University College London

The Dynamic Cell: A High-Speed High-Resolution Microscopy Platform for Biomedical Imaging. 11 Jun 2015

Many groups at UCL are studying the behaviours, physiology and dynamic functional changes of intracellular structures, cells and cell populations. These studies require the ability to combine data acquired at low magnification with data obtained at high spatial resolution. In addition, ultra-fast acquisition rates, together with the ability to manipulate sub-cellular structures and organelles through optical techniques is crucial. Temporal and spatial information is critical for understanding mo st cellular processes. These include the dynamic localization of proteins, including signaling components, the topology of specialized cellular structures and organelles as well as their function and movement. Nano-ablation, FRAP, photo-uncaging and optogenetics provide invaluable techniques to study the mechanical and biochemical dynamics, behaviours and functional properties of cells and tissues in development, in physiology and in disease. Current instrumentation at UCL lacks the sensitiv ity, speed, power and resolution that are available in new generation instruments. The new dynamic cell-imaging platform requested here will be incorporated into the Bloomsbury Consortium for Advanced Light Microscopy, a multiuser Core Imaging Facility at UCL. It will complement existing light imaging resources that include a new super-resolution platform supported by an MRC Next Generation Optical Imaging award.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Open access award 2015/16. 21 Sep 2015

Not available

Amount: £540,000
Funder: The Wellcome Trust
Recipient: University College London

Development of an AAV vector for treatment of Batten disease caused by mutations in TPP1 (CLN2 disease) 25 Aug 2015

Dr Sara Mole of University College London is seeking to develop a gene therapy for CLN2 disease. This is one type of Batten disease, an inherited disease that affects young children. The aim is to prevent the Joss of vision that usually occurs as part of this disease as this will improve the quality of life for the children and their families. The work will build on experience that has Jed to clinical trials for other types of blindness, to make a vector that can deliver a healthy copy of the defective gene tothe eye of an animal model with the same disease. The research will test that this is safe and does not cause any problems in the eye. We will/earn more about the effect of the disease on the eye and the effectiveness of this approach at preventing or slowing down the Joss of vision. The results may help to develop gene therapy to treat other symptoms of the Batten disease and other types of disease.

Amount: £132,626
Funder: The Wellcome Trust
Recipient: University College London

Novel metabolite based therapeutics for improved cholesterol, glucose and reduced weight gain 25 Aug 2015

Obesity, high cholesterol, increased glucose and insulin resistance contribute to a major and growing healthcare threat globally and represent a risk for the development of liver, renal and cardiovascular diseases, as well as Type 2 diabetes. Our project focuses on a new approach to tackling these aberrant metabolic conditions. It is based on studies of a knockout mouse with a remarkable phenotype: lean, resistant to high fat diet weight gain, increased insulin sensitivity and reduced cholesterol. Parallel metabonomic studies led to the discovery of key microbiomederived biomarkers in the knockout mouse. We will test the hypothesis that a microbiome-derived biomarker can be used as a therapeutic to moderate weight gain, plasma cholesterol and glucose and to improve insulin sensitivity.

Amount: £167,160
Funder: The Wellcome Trust
Recipient: University College London

Engineered Treg Therapy for Multiple Sclerosis 25 Aug 2015

Multiple sclerosis is an inflammatory demyelinating condition of the central nervous system. Although several disease-modifying treatments (DMTs) have been approved to reduce the frequency of clinical relapses, most patients continue to clinically deteriorate under current therapy schedules. Autologous haematopoietic stem cell transplantation can have lasting beneficial effects for patients, but the procedure requires aggressive myelo-ablative conditioning which is associated with substantial toxicity. Neither DMTs nor stem cell transplantation can mediate antigen-specific suppression of the immunopathology of MS. Regulatory T cells (Treg) have the ability to suppress unwanted immune responses of T cells, 8 cells and inflammatory myeloid cells. We have previously shown in a murine model that T cell receptor (TCR) gene transfer is a robust technology to generate antigen-specific Treg. In this project, we will use cell engineering technologies to produce Treg that specifically suppress inflammation in the CNS. The planned preclinical work is expected to provide the basis for clinical trials in patients with MS.

Amount: £227,006
Funder: The Wellcome Trust
Recipient: University College London