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Recipients:
University College London
University of Cambridge

Results

Fundamental mechanisms controlling human energy homeostasis 11 Jul 2017

<p>Obesity and associated diseases such as type 2 diabetes, cardiovascular disease and some cancers represent a significant health burden. My overall aim is to identify new therapeutic strategies for severe obesity. Using extensive genetic and clinical data on unique cohorts of individuals at both extremes of the weight distribution (severe obesity and thinness), we will comprehensively map the molecular networks that maintain energy homeostasis and their disruption in disorders of weight regulation. Building on our previous work, we will focus on dissecting cellular mechanisms that converge on leptin-melanocortin signalling using human stem-cell derived hypothalamic neurons. In human studies, we will characterise the effects of specific pathways on eating behaviour, energy expenditure and substrate utilisation. By uncovering the fundamental mechanisms that control human energy homeostasis, our goal is to identify and validate control points that can be targeted to improve outcomes in obesity associated diseases.</p> <p>&nbsp;</p>

Amount: £3,582,289
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fundamental mechanisms controlling human energy homeostasis 11 Jul 2017

<p>Obesity and associated diseases such as type 2 diabetes, cardiovascular disease and some cancers represent a significant health burden. My overall aim is to identify new therapeutic strategies for severe obesity. Using extensive genetic and clinical data on unique cohorts of individuals at both extremes of the weight distribution (severe obesity and thinness), we will comprehensively map the molecular networks that maintain energy homeostasis and their disruption in disorders of weight regulation. Building on our previous work, we will focus on dissecting cellular mechanisms that converge on leptin-melanocortin signalling using human stem-cell derived hypothalamic neurons. In human studies, we will characterise the effects of specific pathways on eating behaviour, energy expenditure and substrate utilisation. By uncovering the fundamental mechanisms that control human energy homeostasis, our goal is to identify and validate control points that can be targeted to improve outcomes in obesity associated diseases.</p> <p>&nbsp;</p>

Amount: £50,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structural cell biology of transport vesicle and organelle biogenesis 11 Jul 2017

<p>Integral membrane protein cargo are constantly moved in coated tubular/vesicluar carriers between the cell's organelles and its limiting membrane in order to maintain membrane identity and function. That these transport processes are of fundamental importance is reflected by the fact that ~30% of mammalian proteins are either components of the vesicle/tubule transport machinery or are its cargo.&nbsp; Coated vesicular/tubular carrier formation including cargo selection requires the interplay of a network of peripheral membrane proteins and membrane components including phospholipids, small GTPases, docking proteins and the cargo itself. The coat must also prepare and facilitate the carrier for fusion with its target. AP2, AP3, COPI and retromer/VARP based coats along with their accessory/regulatory factors are vital for producing a fully functional endosomal system. We will use a combination of X-ray crystallography, NMR and the fast developing techniques of single particle cryoEM and cryo electron tomography allied with biochemical/biophysical studies to formulate theories concerning the architecture, assembly routes and control/regulation of the formation of these four key tubular/vesicular transport carriers. Specific function abolishing mutations designed on the basis of these studies will allow us to test and further explore our theories in cells using a&nbsp; wide range of in vivo techniques.</p>

Amount: £3,445,099
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms and Regulation of RNAP transcription 11 Jul 2017

<p>This grant focuses on four lines of scientific enquiry converging on RNAP function</p> <ol> <li>Characterisation of the molecular mechanisms underlying RNA polymerase and basal factors that facilitate transcription initiation, elongation and termination by using multidisciplinary approaches in vivo and in vitro. This includes using bespoke transcription assays, structure elucidation and a global characterization of the occupancy and transcriptomes.</li> <li>Identification of novel gene-specific factors and characterization of the proteomes of transcription preinitiation- and elongation complexes in vivo. Identification and characterization of RNAP-associated proteinaceous- and RNA regulators.</li> <li>Characterisation of the structure and function of archaeal chromatin formed by A3 and 1647 histone variants. A biophysical characterization of protein-DNA interactions and a whole-genome view of histone occupancy. Focus on the impact of chromatin on RNAP as it progresses through the transcription cycle, and the role of elongation factors to overcome the inhibitory effect of chromatin.</li> <li>Characterisation of factors that modulate RNAP during virus-host interactions. Virus (RIP)- and host (TFS4)-encoded RNAP-binding factors function as global inhibitors of transcription and their mechanism is reminiscent of antibiotics. Using two virus libraries of we want to screen for novel RNAP-binding regulators and use them as molecular probes to dissect RNAP function.</li> </ol>

Amount: £2,029,869
Funder: The Wellcome Trust
Recipient: University College London

The Cambridge History of Medicine 30 Sep 2020

This application is for support to develop a proposal for The Cambridge History of Medicine in six volumes. As General Editor, I will meet with a team of a dozen volume editors at a series of workshops to ask fundamental questions about what the history of medicine is, what it should be, and how best to represent it in these books.

Amount: £96,402
Funder: The Wellcome Trust
Recipient: University of Cambridge

A high-quality connectome of the complete adult Drosophila central nervous system 31 Mar 2020

Building on advances during our successful connectomics collaboration (2016-20), we now propose a very ambitious new goal: a complete, high-quality connectome for the male Drosophila central nervous system (CNS). With Wellcome support and leveraging Janelia’s unique electron microscopy imaging capability, we could turn image data into a fully analysed connectome. This would be the first CNS connectome of an animal with complex motor and cognitive behaviours. In contrast to existing fly datasets, it will be bilaterally complete, include brain and nerve cord and have intact sensory-motor connectivity. This connectome should have an enormous impact on the understanding of CNS-spanning circuitry underlying complex behaviour. We will publicly release initial draft and high-quality versions as soon as they are complete. We will immediately use it to study multisensory integration, memory recall, decision making, modification of brain states, the flexible organisation of motor behaviour, and sexually dimorphic circuits. It will provide a critical resource for > 200 labs worldwide studying Drosophila neurobiology (with impacts on developmental biology and molecular cell atlases) and provide new opportunities for theoretical neuroscientists to study complete, biologically-defined neural networks in a richly investigated organism. We expect general principles, applicable to all nervous systems, including those of humans, to emerge.

Amount: £4,119,965
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neural mechanisms of learning, planning, and decision-making 31 Mar 2020

This proposal examines the neural mechanisms supporting decision-making and prospective planning. We will examine how prefrontal cortex (PFC), hippocampus, and entorhinal cortex (EC) interact to support these processes. We will examine how non-human primates (NHPs) make choices in large decision spaces, particularly when novel choice-values have to be inferred ‘online’. We will test different models of value-coding, particularly whether PFC uses a ‘place-like’ and ‘grid-like’ code to construct cognitive maps of values spaces. We will examine how NHPs make ‘online’ choices when sequentially navigating between stimuli/states as rewards move or paths blocked. We will test whether ‘replay’ provides a neural mechanism supporting model-based planning. We will use Transcranial Ultrasound Stimulation to selectively disrupt regions of PFC/hippocampus/EC to examine its effect on neural selectivity and behaviour. These tasks are high-dimensional, yet amenable to mathematical description, and will be combined with high-density recordings to map these computations. Exp.3 will integrate our home-cage training system with wireless data-logging to record neural data continuously, across tasks and sleep, to examine how neural signatures change across days with learning, and acquisition of ‘learning set’. This provides the technology to continuously map the NHP brain during performance of diverse and naturalistic tasks, radically transforming primate neuroscience.

Amount: £2,580,251
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms of reading development in deaf children 31 Mar 2020

Many severely and profoundly deaf children struggle to learn to read because written text is a visual representation of spoken language, to which they have limited access. I have shown that speechreading (lipreading) relates to deaf children’s reading development. Fully understanding the mechanisms underlying the speechreading-reading relationship is fundamental to harnessing speechreading as a tool to improve deaf children’s reading. My goal is to investigate this mechanism in 1) a longitudinal study, to determine the relationships between speechreading, phonological skills, language skills and reading over time and 2) in neuroimaging studies with deaf children and adults to investigate neural representations of visual speech and written text and the relationships between them. All deaf participants involved in the studies above will use speechreading. A subset will also have learned British Sign Language from an early age. Good quality early sign language exposure is beneficial to reading development in profoundly deaf children. However, the mechanism underlying this relationship is unclear. I will employ parallel methods to those used in the speechreading studies to examine 1) the longitudinal relationships between sign language, fingerspelling and reading and 2) the neural representation of these visual language inputs in deaf children and adults.

Amount: £1,580,335
Funder: The Wellcome Trust
Recipient: University College London

Circuit mechanisms that command and pattern behavioural sequences 31 Mar 2020

Animals accomplish goal-directed behaviours by performing sequences of motor actions. A central goal of neuroscience is to understand how neural circuits regulate behaviour in accordance with external events and internal drives and precisely choreograph diverse actions for a successful outcome. To meet this challenge, I will exploit the unique accessibility of the larval zebrafish and focus on a conserved behaviour – hunting – in which a sequence of discrete, specialised actions mediates pursuit and capture of prey. I will use a powerful experimental strategy that combines cellular-resolution calcium imaging, behavioural analyses, optogenetic circuit manipulations, neuroanatomical tracing and computational modelling to discover how brain-wide circuits operate at the cellular level to flexibly control the expression and coordination of behaviour. This paradigm will enable me to discover (1) how sensory and internal state information are integrated to control the sensorimotor decision to hunt, (2) how specific hunting actions are generated and (3) how command signals operate alongside dynamic sensory inputs to assemble a goal-directed sequential behaviour. Overall, the project will produce a mechanistic, cellular-resolution circuit model that explains how the brain controls and patterns multi-component behaviour. I expect this will reveal fundamental principles about the operational logic of the nervous system.

Amount: £2,078,748
Funder: The Wellcome Trust
Recipient: University College London

Targeting the gut in metabolic disease 31 Mar 2020

This project aims to identify new strategies to target the gut for the treatment of type 2 diabetes and obesity. Intestinal hormones regulate intestinal nutrient absorption, insulin secretion and appetite, and therapeutics based on the gut peptide GLP-1 are widely used for type 2 diabetes and obesity. Bariatric surgery causes weight loss and resolves diabetes at least in part via gut endocrine changes. This project will characterise human enteroendocrine cells using intestinal organoid cultures, building on our previous work using transgenic mouse models. To identify cells of interest, organoids will be engineered by CRISPR/Cas9 to express fluorescent sensors driven by hormonal promoters, allowing cellular analysis by transcriptomics, electrophysiology and real-time fluorescence imaging of e.g. Ca2+ and cAMP. We will characterize nutrient sensing pathways and identify receptors and signaling pathways potentially modifiable therapeutically. Using mouse and human tissues, we will identify circuitry involved in bidirectional cross-talk between gut endocrine cells and enteric/autonomic nerves. Building on our new methods to analyse peptides and the low molecular weight proteome by mass-spectrometry, we will investigate how plasma peptides respond to nutrient ingestion in health and metabolic diseases including diabetes, obesity, lipodystrophy and anorexia nervosa, and following bariatric surgery or dietary calorie restriction in obesity.

Amount: £2,381,203
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cellular dissection of Plasmodium falciparum erythrocyte invasion 31 Mar 2020

Plasmodium falciparum parasites still cause nearly half a million deaths each year. The repeated emergence of antimalarial drug resistance and the lack of a highly effective vaccine mean that there is an urgent need to identify new intervention targets. Erythrocyte invasion is an excellent target as it is essential for both parasite survival and for malaria pathology. Invasion involves multiple parasite ligands, but little is known about their function at the cellular level and even less about how they fit into the broader network of invasion proteins. This proposal will revolutionise our understanding of the function of two families of P. falciparum invasion ligands, the EBLs and the RHs, that are together responsible for the key decision point in the invasion process. The key goals are to: Systematically dissect functional equivalence between EBLs and RHs Establish the roles that EBLs and RHs play in discriminating between erythrocyte variants within and between humans Use innovative combinatorial approaches to move from a gene to a network understanding of EBL and RH function. The proposal will provide a step change for the field, both biologically and technically, and will identify new candidates for testing in a rationally designed, multi-component invasion-blocking vaccine.

Amount: £2,214,779
Funder: The Wellcome Trust
Recipient: University of Cambridge

Bridging the gap: biophysical models of human frontotemporal lobar degeneration 31 Mar 2020

To treat and prevent dementia in patients, it is essential to understand how microscopic changes in the human brain cause complex cognitive and behavioural disorders. My program addresses this critical gap in translational research, to facilitate clinical application of basic science discoveries. I have three goals, set in the context of frontotemproal dementia and progressive supranuclear palsy. First, I will develop quantitative biophysical models of human brain function that capture key cellular and pharmacological pathologies in vivo, with regional, laminar and synaptic specificity. These models of degenerating neuronal circuits are informed by individual measures of synaptic density (PET imaging with a SV2a ligand), GABA and glutamate (ultrahigh-field MR spectroscopy). They are optimised in vivo by inversion to magnetoencephalography, and tested post-mortem against neuropathology. This synergy of multi-modal imaging, together with Bayesian model comparison of Dynamic Casual Models, means one can drill down to the best mechanistic model of the human cognitive disorder. Second, I will show how harmful effects of dementia like apathy can be explained in terms of changes in synaptic density and loss of precision in hierarchical brain networks. Third, I will I demonstrate the readiness of my approach for experimental medicine, through longitudinal designs and pharmacological interventions.

Amount: £2,025,694
Funder: The Wellcome Trust
Recipient: University of Cambridge

Exploring mitochondrial metabolism in health and disease using targeted biological chemistry 31 Mar 2020

The molecular mechanisms by which mitochondrial reactive species, metabolites and redox signals contribute to physiology and pathology are unclear. This is in large part because these processes are difficult to assess and modulate in vivo. Our goals are to establish general chemical biology approaches to determine the mechanisms of mitochondrial physiology and dysfunction in vivo and from this develop new therapeutic strategies. The aims are based on the success of our previous Joint Investigator Award, but the specific chemical biology approaches to be used, the insights to be attained and the models have been refined and developed, based on our work over the past four years. These goals will be achieved by addressing three research challenges in cells and in vivo: A: Can we determine how mitochondria operate during normal physiology, and are disrupted during pathology, by targeting probes to measure reactive species and alterations to signaling pathways? B: Can targeting bioactive molecules to mitochondria prevent pathological disruption of mitochondrial function and generate potential therapies? C: Can the above methods to monitor and modulate mitochondrial function be assessed in animal models of human diseases and thus drive the development of rational, translatable therapies?

Amount: £875,659
Funder: The Wellcome Trust
Recipient: University of Cambridge

How cell migration and differentiation are coordinated during morphogenesis 31 Mar 2020

During development the embryo needs to generate functional organs composed of many different cell types, often originated in different embryonic location. Thus, it is clear that cell differentiation and migration need to be tightly coordinated, although they are often studied as independent processes. Here I will test the hypothesis that cell migration and differentiations are coordinated by tissue mechanics in vivo. Specifically, I will challenge the current view that cell migration is the result of differentiation, by testing instead whether the reverse occurs, i.e. migration controls differentiation. I will use neural crest cell, a multipotent embryonic cell population in which cell differentiation is always linked to cell migration. One of the problems to study biomechanics in vivo is the limited number of tools to measure and modify mechanical properties in vivo. Here I will develop new tools to analyse and change tissue stiffness in vivo. We will analyse how these mechanical changes influence cell migration and differentiation, and we will identify the molecular response elicited in the neural crest cells. We expect that this multidisciplinary project will provide answers to a central yet unresolved question in developmental biology: how cell fate and migration are integrated during embryo development.

Amount: £1,734,742
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms and roles of transmissible RNA 04 Mar 2020

Protein coding and non-coding RNA can spread between cells and tissues of an organism. RNA mobility between organisms has been documented within and among different kingdoms of life including fungi, plants and animals. However, the underlying mechanisms and roles of such transmissible RNA are poorly understood. Our recent studies demonstrated that honeybees share biologically active RNA among members of the hive through secretion and ingestion of worker and royal jellies. The jellies harbor naturally occurring exogenous (e.g. viral) and endogenous RNA. These findings suggest that RNA transfer plays a role in social immunity and signaling between honeybees. Therefore, the key goals of this proposal are: to establish a metabolic RNA labeling system in honeybees; and to apply this system to study natural RNA transfer-mediated antiviral immunity and impacts on the physiology of recipient bees. To achieve these goals, I will combine RNA biology techniques and imaging with high-throughput sequencing to establish a functional transmissible RNA pathway in honeybees. This project will provide knowledge and tools that will enable studying the biology of RNA flow in other organisms, including humans, in diverse biological aspects; hence, will ultimately contribute to the development of RNA-based applications to promote health and disease control.

Amount: £1,393,480
Funder: The Wellcome Trust
Recipient: University of Cambridge

Open Access Award 2019/20 30 Sep 2020

Not available

Amount: £20,000
Funder: The Wellcome Trust
Recipient: University College London

Open Access (COAF) award 2019/20 30 Sep 2020

Not available

Amount: £813,243
Funder: The Wellcome Trust
Recipient: University College London

The Impact of Pneumococcal and Malaria Vaccines on Bacterial Resistance, Febrile Illness and Antibiotic Usage in Young Children In Malawi 30 Nov 2019

Across much of sub-Saharan Africa, pneumococcal disease (otitis media and pneumonia) and malaria are leading causes febrile illness, and therefore drivers of both appropriate and inappropriate antibiotic use. Prevention through vaccination has the potential to influence antimicrobial resistance (AMR) both directly and indirectly. We are in a unique position to leverage two large funded cluster-randomised vaccine evaluations in Malawi: 13-valent pneumococcal conjugate vaccine (PCV13) schedule change (3+0 to 2+1; extending immunity and potentially herd protection); and RTS,S malaria vaccine introduction. We will ask what are the direct and indirect selective effects of pneumococcal and malaria vaccines on antibiotic resistance, febrile illness and antibiotic usage in young children in Malawi? We will determine whether in children S. pneumoniae carriage isolates; the upper respiratory tract resistome; and stool carriage of extended spectrum beta-lactamase (ESBL) E. coli or Klebsiella. We will assess whether the pneumococcal or malaria vaccines alter the frequency of febrile illness and antibiotic use in children

Amount: £764,996
Funder: The Wellcome Trust
Recipient: University College London

Open Access (COAF) Award 2019/20 30 Sep 2020

Not available

Amount: £1,029,579
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Biosocial Lives of Birth Cohorts 28 Jan 2020

This four year project examines birth cohorts as sites of knowledge, practice and participation in the UK, Europe and Latin America. It aims to understand how they provide an infrastructure for and are a technology of biosocial science. It is the first study to take birth cohorts as an object of ethnographic inquiry in comparative national contexts. In an era of post-genomics, studies that follow research participants over their lifetimes have become vital to understanding how material and social environments ‘get under the skin’ and are dynamically shaped across the lifecourse. This is increasingly described as ‘biosocial science’, reflecting the importance to this field of the interaction between social and biological factors. Whilst a notion of the biosocial is not new, singular nor uncontested it is now being re-shaped in global research terrains with longitudinal cohort studies as important tools and technologies. By examining the ‘biosocial lives’ of birth cohorts in the global north and south, I will provide insight on the socio-cultural specificity of these developments. Comparison will inform theorisation of what the biosocial is, whilst an ethnographic perspective will facilitate methodological innovation in examining and intervening on birth cohort research and how biosocial science is coming into being.

Amount: £1,009,755
Funder: The Wellcome Trust
Recipient: University College London