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Results

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

How are chromosomes held together by cohesin?. 07 Jul 2015

1. How are chromosomes held together? 2. How does cohesin associate with chromatin and hold sisters together? 3. Mechanism of loading? 4. How is cohesion established? 5. How is dissociation regulated by acetylation? 6. Whatis the role of kinetochore cohesin during meiosis? 7. What is the structure ofcohesin and partners? 8. How does condensin hold together the DNAs of individual chromatids?

Amount: £3,174,432
Funder: The Wellcome Trust
Recipient: University of Oxford

Moving folded proteins across membranes. 07 Jul 2015

The Tat (twin arginine translocation) system, which I co-discovered, is a highly unusual protein transport pathway that is able to export folded proteins across the cytoplasmic membrane of bacteria. It is required for the virulence of many common pathogens. A central question in the Tat field is howthe transporter is able to actively transport folded proteins across the membrane bilayer without significant ion leakage. Tat transport involves threetypes of small integral membrane proteins, multiple copies of which dynamically assemble in the presence of a substrate protein to form a transient transport complex. It is this transport complex that is key to understanding the mechanism of Tat transport. Although we have recently determined high resolution structures of the individual Tat components, the assembled translocation site has been considered to be too ephemeral and unstable to be isolated and studied. In major methodological breakthroughs my group has identified ways of following the behaviour of the complex in real time in living cells, of stalling the transport complex in the assembled state, and of solubilizing the translocation complex from its native membrane environment. I now aim to exploit these advances to answer the key questions about the mechanism of Tat transport: (1) What is the structure of the assembled Tat translocation site? (2) What, based on this structural data, is the physical mechanism of substrate transport across the membrane and of energy transduction to drive transport? (3) What are the component steps in the Tat transport cycle, what are the structural changes occurring at each step, and what molecular features control the interconversion between the steps?

Amount: £1,252,987
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular mechanism and regulatory function of protein coding gene transcriptional termination in mammalian genomes. 07 Jul 2015

The enormous facility with which mammalian genomes can be sequenced has outstripped our understanding of gene function in a genomic context. This disconnect between genomics and gene mechanism is especially evident in understanding how gene transcription units are defined. The major vision behind my proposal is to determine which genes terminate transcription by which mechanism and how this impacts on gene expression. To achieve this we will combine genomic analysis of nascent transcription with mechanistic studies that rely on molecular biological and biochemical analysis. Aims: 1) We will define in molecular detail the common mechanisms that mediate efficient transcriptional termination. 2) We will annotate which termination mechanisms act on which protein coding genes and how this may impact on their expression. 3) Many previously considered ubiquitous termination factors only affect a subset of protein coding genes. We aim to understand why this is the case and how it relates to gene regulation. 4) Transcriptional termination directly interconnects with all other stages of transcription. We will investigate the molecular basis of these interconnections. 5) Loss of termination causes read-through transcription (fused transcripts) a feature ofcancer cells. This suggests that cancer causes breakdown in normal transcription unitdefinition. We aim to better understand why termination is defective in cancer.

Amount: £2,242,936
Funder: The Wellcome Trust
Recipient: University of Oxford

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

Time to Decide. 01 Apr 2015

The objective of this proposal is to investigate the temporal dynamics of simple perceptual decisions in Drosophila, with a view toward uncovering general mechanisms of neural information processing at timescales from hundreds of milliseconds to several seconds. In his classical essay The Problem of Serial Order in Behavior, the psychologist Karl Lashley emphasized the ubiquity of brain processes that unfold over time: Temporal integration is not found exclusively in language; the coordination of leg movements in insects, the song of birds, the control of trotting and pacing in a gaited horse, the rat running the maze, the architect designing a house, and the carpenter sawing a board present a problem of sequences of action which cannot be explained in terms of successions of external stimuli. In spite of the ubiquity of the problem, there have been almost no attempts to develop physiological theories to meet it. Although Lashley wrote this passage more than 60 years ago, the fundame ntal problem of how activity sequences are generated remains largely unsolved. Temporal processing is integral also to decision-making because the information necessary to commit to a choice is rarely available all at once but must be gathered over time. A large literature, whose beginnings stretch back to the 19th century, documents systematic variations in the speed of perceptual judgments with stimulus strength: easy decisions, based on strong, unambiguous sensory data, tend to be fast; di fficult decisions, based on weak or conflicting data, tend to be slow. This difficulty-dependent cost of decision time is thought to reflect an underlying need to construct time-averaged sensory representations. Just like engineers average signals over time to reduce the effects of contaminating noise, the brain appears to improve its signal-to-noise ratio by integrating information from sequential samples. The duration of the integration period depends on the quality of the sensory data and the desired response accuracy or confidence. Beautiful as these ideas are, the neural mechanisms that allow neurons to accumulate information, compare the accumulated signal to a response criterion, and discharge behaviour when the criterion is met remain elusive. The complexity of vertebrate brains, the difficulty of molecular interventions, and the effort required to generate and analyse genetic variants have presented serious barriers to progress. These barriers have begun to ero de with our recent discovery that fruit flies, like mammals, take longer to commit to difficult perceptual choices than to easy ones, and that quantitative relationships link speed, accuracy, and task difficulty. The exact mathematical form of these relationships is predicted by integrator models that were originally formulated to describe human behaviour. Drosophila thus appears to accumulate sensory data in the lead-up to a choice, making this type of temporal processing amenable to genetic di ssection. A small screen of candidate genes uncovered an unexpected role for FoxP in decision-making. FoxP mutants are slower to commit than wild-type flies, and, despite taking longer, are also more error-prone - precisely the constellation of symptoms one might expect in an a

Amount: £2,389,037
Funder: The Wellcome Trust
Recipient: University of Oxford

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

Genetic dissection of sexual behaviour. 03 Dec 2014

1. What are your research questions? We use Drosophila courtship behaviour to study how sex-specific neural circuitry and behaviours are established during development by the action of complex networks of genes. Our studies focus on two pivotal transcription factors of the sex-determination hierarchy, fruitless (fru) and doublesex (dsx) that act together to specify and configureboth the anatomy and physiology of sex-specific neural circuitry. We employ cutting edge genetic, molecular and behavioural approaches to understand how fru and dsx direct the genetic programs responsible for the assembly of the underlying dimorphic circuitry that governs sex-specific circuit function. Ultimately we aim to understand how activity in functioning dimorphic neural circuits gives rise to a different sex-specific behavioural repertoire in the male and female fly.We will address the following specific questions: What are the regulatory principles governing the assembly of sex-specific circuits? Biological differences between males and females result from two processes: sex determination and differentiation. Sex determination controls whether the male or female sexual differentiation pathway will be followed. Sex differentiation involves many genetically regulated, hierarchical developmental steps. The sex of an animal determines its sexual behaviour and orientation. In the fruit fly, sexual differentiation of the neural circuits underlying sexualbehaviors is dependent on the action of the Dsx and Fru transcription factors. Selective expression of Dsx and Fru define cell-type-specific developmental programs that govern connectivity and lay the foundations through which innate sexual behaviors are genetically predetermined. We are investigating the fundamental question of how the Fru and Dsx transcription factors achieve this by regulating the expression of target genes. Since dsx is both structurally and functionally conserved throughout the animal kingdom, similarities in the molecular mechanisms that control sexual differentiation are likely to be identified. What are the neural circuits that encode sex-specific behaviours? Sexually dimorphic behaviours arise from anatomical and functional differencesin neural circuits. In some cases, the sex differences are qualitative such that particular neurons are unique to one sex, in others a quantitative sex difference may represent a dimorphism in the same cell or the molecular characteristics of shared neurons. In the fly, manyof these dimorphisms reside in central brain neurons. This suggests that males and females detect many of the same external signals but process them differently to produce distinct behavioural responses. We are interested in how these sex differences relate to sexually dimorphic behavioural outputs. Addressing these questions in the fly is now a realistic goal. By identifying the neural and molecular components of sex-specific neural circuits, and mapping functional connectivity, we can define causal relationships between circuit activity and sexual behaviour.

Amount: £1,549,999
Funder: The Wellcome Trust
Recipient: University of Oxford

Exploring the Mechanisms of Distributed Spontaneous Brain Activity. 03 Dec 2014

My research focuses on answering questions about the mechanisms that underlie widely-distributed networks of neural activity. I develop novel techniques for empirically characterizing whole-brain activity using multi-modal imaging and probabilistic inference, in combination with computational network models as mechanistic explanations of these observations. The research in this proposal will change the time-scales at which we can answer these questions, enabling investigation into the volatil ity of spontaneous brain activity, and the role of homeostatic synaptic plasticity in maintaining spontaneous activity at a suitable operating point. I will also investigate the use of measures of brain activity stability and homeostatic control in the clinical setting. I will build novel analytic methods and biophysical models, and use experimental investigations incorporating human and multi-cellular rodent recordings. I will: (i) characterise spontaneous brain activity on fast (sub-second) time scales; (ii) propose mechanisms of how these characteristics arise as an emergent property from anatomical connectivity; (iii) investigate the nature of the interactions within and between brain areas; (iv) propose a role for homeostasis through plasticity in regulating whole-brain activity; and (v) assess the utility of measures of brain activity stability and homeostatic control as biomarkers in disease.

Amount: £796,462
Funder: The Wellcome Trust
Recipient: University of Oxford

The melanopsin signalling pathway in ocular, circadian and sleep physiology: mechanisms to clinical application. 03 Dec 2014

Our broad vision is to: Provide a detailed understanding of how melanopsin-based photosensitive retinal ganglion cells (pRGCs) encode and signal light information for the regulation of ocular, circadian and sleep physiology and to translate this knowledge into clinical and public understanding for the improvement of health. A seven-year programme of work is summarised in Figure 1. These aims align very closely with two of the Wellcome Trusts major challenges: (i) Understanding the brain; (ii ) Maximising the health benefits of genetics and genomics. Aim 1: Define the impact of ocular disease on human sleep/wake timing and mood. Despite the critical importance of the eye in regulating human circadian rhythms, sleep, alertness and mood [1], these critical behaviours are rarely addressed in clinical ophthalmology and specific guidelines relating to the disruption of these faculties in ocular disease are entirely lacking. To redress this omission, a Wellcome Trust Enhancement Aw ard allowed us to initiate such a study in January 2013. We have established the recruitment protocols and developed the infrastructure for both primary [2] and advanced [3] phenotyping of sleep and circadian abnormalities across a broad range of ocular diseases. As of June 2014 we have the following patient numbers recruited into the study: Cataract (n=961); Glaucoma (n=191); AMD (n=326); Diabetes II (n=446); Anophthalmia (n=12); RP (n=46). The results from the continuation of these studies wil l permit us to: -Build a comprehensive database linking specific ocular diseases, and disease states, to sleep and mood problems. -Establish which interventions are the most effective in improving these abnormal sleep states (see Aim 6). -Develop national evidence-based guidelines for clinical ophthalmology. We stress, disrupted sleep is closely linked to the added susceptibility of a range of co-morbid pathologies, including cognitive decline, depression, attentional failures, metabo lic and immune problems, and heart disease [4]. Thus ocular disease not only results in visual dysfunction but has the potential to inflict multiple additional pathologies, all of which can lead to major deficits in health and quality of life. Aim 2: Address the role of melanopsin in ocular light protection. The eye has several mechanisms to protect itself from light damage [5; 6], but the photopigment systems that activate these responses remain poorly defined. We reasoned that OPN4 may play an important role. Microarray studies were undertaken on the retinae of mice either lacking melanopsin (Opn4-/-) or wild-type controls (Opn4+/+) following light exposure. Multiple genes that normally protect the retina from light damage were highly up regulated in Opn4+/+ mice but this response was absent in Opn4-/- mice. Building upon these striking findings we will address: -Are Opn4-/- animals more susceptible to light-induced retinal damage? Following different light treatments the e ye/retina of Opn4-/- mice will be examined histologically and using TUNEL staining to detect DNA fragmentation and other markers of light-induced damage. -How is OPN4 mediating this protective effect? Light mediates an increase in retinal dopamine, which may or may not be mediated by OPN4 [7; 8]. We

Amount: £2,912,157
Funder: The Wellcome Trust
Recipient: University of Oxford

I-brain: A neuropsychological analysis of social attention and cognitive control. 03 Dec 2014

I will ask 2 basic science and 2 translational questions that are key for understanding social cognition. The basic questions ask: (i) how can attention be controlled in social contexts and (ii) what are the necessary neural substrates of social attention? Previously I have shown that personally related stimuli can strongly determine the allocation of attention based on a distinct neural circuit. This then provides a model system for understanding social attention.The translational questions ask: (iii) can a clinically applicable screen for social cognition and attention be developed, and (iv) can problems in social attention be rehabilitated? These questions are addressed by evaluating effects of brain lesions on biasesto personally relevant stimuli using detailed behavioural measures combined with structural and functional MRI, exploiting a clinical screening programme for patient recruitment. The new screening tool developed for this, plus proofof principle rehabilitation procedures, will provide specific translational deliverables.

Amount: £1,334,539
Funder: The Wellcome Trust
Recipient: University of Oxford