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Award Year:
2013
Recipients:
University of Cambridge
Currency:
GBP

Results

Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at the University of Cambridge: Support for the 2013 MPhil Appointments. 18 Nov 2013

We propose an innovative training scheme for Translational Medicine and Therapeutics (TMAT) which builds on the exceptional conjunction on the Cambridge campus of leading scientists and clinical specialists, with an industrial research environment embraced both by international pharmaceutical and local biotech companies. Much of this is found under the same roof, the Addenbrookes Centre for Clinical Investigation (ACCI), with a track record of integrated training: academic with industrial, clinical with scientific, pharmacology & therapeutics with patient-based specialties. The novel TMAT programme will attract the brightest candidates at several levels of seniority, ranging from MB PhD students to clinical lecturers, some wishing translational skills in their chosen specialty, others not yet differentiated who may become future leaders and teachers of TMAT. Each trainee will have a customised programme. Part of this will be a bespoke, modular MSc modelled on the well-known small-group lectures and supervisions of the Cambridge final year undergraduate courses. However the centrepiece for most candidates will be a PhD including formal teaching in a wide range of translational and pharmacological skills, and a project which takes proof-of-concept studies in cell or animal systems forward to proof-of-concept studies in humans. We have assembled an outstanding faculty of PhD supervisors spanning a wide choice of skills and experience in basic and clinical science. All trainees will have the opportunity for hands-on exposure to the design and conduct of experimental medicine studies investigating the therapeutic potential of new drugs, in collaboration with our industrial partner, GlaxoSmithKline (GSK). Our product will be a new generation of clinician scientists with 360-degree vision of the complex landscape of modern therapeutic medicine, who can rise to the challenges and opportunities of 21st century drug development.

Amount: £12,234
Funder: The Wellcome Trust
Recipient: University of Cambridge

Targeted mRNA Trafficking in Pathfinding Axons of the Developing Visual System. 24 Jun 2013

Building properly wired neural circuits involves guidance of axons towards synaptic targets in the brain. In the growth cone of pathfinding axons, targeted mRNA transport and localised translation is important for autonomously regulating navigational responses tocertain extracellular guidance cues. Still however, axonal mRNA trafficking remains poorly understood. We know very little about which mRNAs are differentially trafficked on guidance cue stimulation or mechanisms underpinning axonal mRNA transport. Using the well-characteriseddeveloping visual system as an experimental platform, this research proposal aims to explore the functional and mechanistic basis of targeted mRNA trafficking during axon guidance. We

Amount: £159,401
Funder: The Wellcome Trust
Recipient: University of Cambridge

Optogenetic Control of Immune Cell Signalling 24 Jun 2013

Though the components of the T-cell antigen receptor (TCR) signalling pathway have been fairly comprehensively characterised since the 1980s, the precise spatio-temporal dynamics of T cell activation remain to be described. Using optogenetic control of TCR proximal signalling, we intend to manipulate T-cellactivation to help address some of these outstanding issues. Key goals include: 1. The establishment of light-inducible cell lines. To date, we have created and tested a number of LAT-based constructs. Completion of this goal would involve the transfer of these constructs to a wildtype Jurkat T cell line. 2. Determination of the role of signal source within the cell. Using our light-switchable constructs we hope to test whether sustained receptor proximal signalling is necessary for T cell activation. This will be accomplished be relocalising constructs within the cell and measuring the level of cell activation. 3. Determination of microcluster formation kinetics. We intend to use time course experiments to characterise the formation of TCR signalling microclusters. 4. Assess involvement of the actin cytoskeleton. By measuring the association kinetics of signalling components relative to the cytoskeleton we aim to elucidate the role of the cytoskeleton in TCR signalling.

Amount: £159,305
Funder: The Wellcome Trust
Recipient: University of Cambridge

Support for a Wellcome Trust/Academy of Medical Sciences Internship. 16 Sep 2013

To investigate the mechanisms involved in the developmental programming of obesity and insulin resistance in peripheral and central tissues of offspring of obese mothers using a mouse model of maternal diet-induced obesity.

Amount: £5,490
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge 16 Sep 2013

Regular physical activity prevents cardiovascular disease, diabetes, obesity, some cancers, as well as being important for bone health, mental health and well-being. Despite its importance, the proportion of adults who are sufficiently active in the UK remains low. Promoting active travel (walking and cycling) may be one means to shift physical activity levels, and realise large population health benefits. A public health perspective emphasizes the importance of changing the wider built and social environment in order to achieve population shift. The present evidence base is biased towards individual-level interventions. Work that does consider the environment is largely limited to cross-sectional studies which have no ability to demonstrate causation. The effects of travel on physical activity and health are poorly described. This fellowship will use two established natural experimental studies to test longitudinal associations between changes in the environment and changes in: mediators, travel behaviour and physical activity. It will also test the longitudinal association between active travel and indicators of health or well-being, as well as characterising the long-term benefits in population health from a shift to active travel. This will inform the evidence base concerning the promotion of active travel (by environmental change) to improve population health.

Amount: £274,582
Funder: The Wellcome Trust
Recipient: University of Cambridge

The regulation of chromatin structure and function. 10 Jul 2013

We will use the power of functional genetics and genomics in C. elegans to address fundamental questions in chromatin regulation and transcriptional control, by analysing epigenetic state and function in wild-type and mutant animals and tissues. Chromatin is the organization of genomic DNA with histones that can have a wide range of post-translational modifications and hundreds of associated proteins and RNAs. The composition and structure of chromatin determines activity state and is central to the control of transcription, the expression of cell identity, the maintenance of pluripotency, and the transformation to cancer. However, our knowledge of chromatin composition and understanding of chromatin regulator function is still at a basic level. C. elegans has a complement of core chromatin factors very similar to that of humans (many with existing mutants), a small well-annotated genome (30x smaller than human), RNAi for loss of function studies, and well-characterised cell fates. We will combine the strengths of model organism genetics with genome-wide chromatin phenotyping to unravel mechanisms of chromatin regulation that will have impact across animals. Our specific aims: 1. More comprehensively characterize properties of wild-type chromatin and discover regulatory principles that operate in cell fate determination and differentiation. 2. Use global chromatin phenotype profiling of mutants to unravel functions and mechanisms of action of conserved chromatin regulators important for human biology. 3. Profile transcription initiation and elongation to investigate the developmental regulation of promoters, enhancers, and non-coding transcription, and use transgene constructs for their functional analyses.

Amount: £3,232,727
Funder: The Wellcome Trust
Recipient: University of Cambridge

Multi-locus models of pathogen evolution. 29 May 2013

Time-resolved genetic data offers a new and exciting opportunity to study pathogen evolution. Sequencing a population at multiple time points reveals genetic changes as they occur. Mathematical models based upon the dynamics of evolutionary systems allow for more accurate identification of alleles under selection, and better measurements of the magnitude of selection, than have previously been achieved. I will develop models to interpret time-resolved genetic data, so as to better understand the evolution of pathogens. Unified by the theme of modelling rapid evolutionary dynamics, this work will make progress in understanding multiple pathogenic organisms. Specifically, this project will use high-coverage sequence data to quantify the role of selection in the intra-patient evolution of influenza, relevant to the emergence of new pandemics. It will examine how immune and drug pressure, acting upon the HIV virus, affect viral diversity in the early stages of an infection. The project will develop methods to better interpret genetic data from drug resistance experiments, in order to identify genomic factors leading to drug resistance in malaria parasite, helminthes, and leishmania. Finally, I will investigate the potential of multi-locus genetic models of evolution to understand, and to predict, the evolution of seasonal influenza.

Amount: £650,845
Funder: The Wellcome Trust
Recipient: University of Cambridge

Resolving ubiquitin-dependent degradation of misfolded proteins using advanced single-molecule techniques. 05 Jun 2013

My proposed research seeks to understand the links between degradation of protein aggregates and the ubiquitin-proteasome pathway. The project entails three goals. The first goal involves establishing a fluorescence-based system to detect individual interactions between aggregates and proteasomes. To achieve this, I will initially receive training on proteasome purification and examine how to modify proteins with specific ubiquitin chains. Subsequently, I will explore different fluorescence labe lling systems and optimise a labelling strategy for protein aggregates and the proteasome without disrupting their integrity. The fluorophores selected should be bright and photostable to be compatible with the single-molecule instruments. This single-molecule fluorescence system will be used to establish a method that can reveal interactions between individual protein aggregates and a single proteasome to determine the efficiency of degradation for different types of aggregates. The second goal will focus on aggregate degradation in cells using three-dimensional superresolution imaging. Heterogeneous interaction between aggregates and proteasomes can be resolved to determine whether certain types of aggregates can inhibit the proteasome. Finally, I will focus on cell lines with mutations on key Parkinson's disease-related genes, and establish whether aggregate degradation is affected. Identifying altered degradation in these cells will relate proteasome functions directly to disease s tates.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Amani Research Station - the post-colonial period. A witness seminar. 30 Aug 2013

Support is sought to hold a half-day witness seminar to be held in Cambridge on August 5th 2013 on the period of Africanisation (late 1950s to 1970) at the Amani research station in Tanzania - then the main malaria research site in formerly British Africa. The seminar will involve at least 10 expatriate scientists and technicians, women as well as men, who worked and lived in Amani from the late 1950s to the early 1970s, and who handed over their tasks to East African colleagues. The s eminar will be recorded and transcribed and annotated bythe applicants. (This witness seminar application will be followed by an independent application by Drs Mangesho and Okwaro for a twin event to be held at Amani research station, bringing together the East African scientists and technicians who worked on the site at the time.)

Amount: £4,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mutational signatures of DNA damage and repair processes. 17 Apr 2013

DNA in all cells is prone to mutagenesis, with somatic mutations making key contributions to human diseases such as cancer and neurodegenerative diseases, and to aging itself. Mutations are the consequence of exogenous or endogenous mutagenic influences (including radiations and DNA-damaging chemicals) and also result from enzymatic DNA modifications or low fidelity DNA synthesis by specialized DNA polymerases. Mutations are generally prevented by the cellular DNA-repair machinery and defective functioning of this machinery can markedly increase mutation rates. Different mutational processes leave different, characteristic signatures of somatic mutations on the exposed cellular genome. Notably, recent analyses of cancer genomes have revealed several novel mutational signatures, the biological bases of which are predominantly unknown. To define somatic mutational processes operative in cells, and in particular their influences on human disease, we propose to systematically survey, at th e genome-wide level, mutational signatures generated by exposures to known or putative human carcinogens, defective DNA repair/editing processes or dysfunction of other cellular processes. These studies will provide a set of mutational signatures with known underlying causes for subsequent matching to signatures found in normal or diseased human cells and will expand our knowledge of how various cellular components influence mutagenesis.

Amount: £1,027,551
Funder: The Wellcome Trust
Recipient: University of Cambridge

Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at the University of Cambridge: Support for the 2013 Academic Foundation Year appointments. 25 Mar 2013

We propose an innovative training scheme for Translational Medicine and Therapeutics (TMAT) which builds on the exceptional conjunction on the Cambridge campus of leading scientists and clinical specialists, with an industrial research environment embraced both by international pharmaceutical and local biotech companies. Much of this is found under the same roof, the Addenbrookes Centre for Clinical Investigation (ACCI), with a track record of integrated training: academic with industrial, clinical with scientific, pharmacology & therapeutics with patient-based specialties. The novel TMAT programme will attract the brightest candidates at several levels of seniority, ranging from MB PhD students to clinical lecturers, some wishing translational skills in their chosen specialty, others not yet differentiated who may become future leaders and teachers of TMAT. Each trainee will have a customised programme. Part of this will be a bespoke, modular MSc modelled on the well-known small-group lectures and supervisions of the Cambridge final year undergraduate courses. However the centrepiece for most candidates will be a PhD including formal teaching in a wide range of translational and pharmacological skills, and a project which takes proof-of-concept studies in cell or animal systems forward to proof-of-concept studies in humans. We have assembled an outstanding faculty of PhD supervisors spanning a wide choice of skills and experience in basic and clinical science. All trainees will have the opportunity for hands-on exposure to the design and conduct of experimental medicine studies investigating the therapeutic potential of new drugs, in collaboration with our industrial partner, GlaxoSmithKline (GSK). Our product will be a new generation of clinician scientists with 360-degree vision of the complex landscape of modern therapeutic medicine, who can rise to the challenges and opportunities of 21st century drug development.

Amount: £35,478
Funder: The Wellcome Trust
Recipient: University of Cambridge

Imperfect choice and the brain: uncertainty, value and decision-making. 06 Nov 2013

I will combine theoretical models from economics and psychology with tools from experimental neuroscience to isolate the factors and describe the computational processes that lead to uncertainty in the estimations of value used to guide value-based choice. I will test if the same neural network involved in value computation also represents the levels of uncertainty that emerge during the value comparison process and how uncertainty governs levels of subjective confidence in choice. I aim to diss ect the neural circuit that enables humans to be aware of the level of uncertainty in their value-based decision (measured as level of confidence), an ability that confers the critical advantage of taking corrective actions. I will test how the brain deals with incomplete information when constructing value estimates and more specifically whether (like perceptual decision-making) this fragmented information is combined according to Bayesian (optimal) integration scheme. I will also explore the r elationship between uncertainty and suboptimality in economic or financial choices, testing how noisy value estimates trigger inconsistency in value-based decisions. The ultimate goal of this research agenda will be to produce a coherent and mechanistic account of how we assign values and make choice in a mist of uncertainty.

Amount: £972,601
Funder: The Wellcome Trust
Recipient: University of Cambridge

Improving Public Awareness of the Science of Food addiction. 20 Aug 2013

We believe that the concept of food addiction, which has gained a great deal of currency despite its poor scientific support, could be explored in a new and exciting way through drama. We want to develop a radio play which examines the science of food addiction and the development of scientific ideas, research and careers, through the story of a mildly hapless neuroscientist who unexpectedly finds himself appointed the government's food addiction czar. Despite the fame and fortune attached to th is position, he is forced to watch while the science is twisted to suit the demands of policy.

Amount: £3,850
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fertilization Through a Looking Glass: a sociology of UK IVF in the late-twentieth century. 28 Jan 2013

In vitro fertilization is one of the most successful technological innovations of the late-twentieth century, and yet is one whose recent historical present remains largely unanalysed. Five aspects of this history are combined in the proposed research, which aims to chart the emergence of clinical IVF in the UK during a distinctive era of basic scientific investigation of mammalian developmental biology. UK scientists and clinicians, as well as policy makers, have played a leading role in the de velopment and translation of IVF technology, but while doing so faced unique challenges and dealt with unprecedented questions concerning the ethical, social, technological, scientific, and cultural implications of this unique technology. Drawing on interviews with many of the key players involved in IVFs translation into clinical practice, and supplementing these with a range of other sources, the research explores how the introduction of IVF was navigated, and what can be learned from this unu sual case of rapid technological change affecting the basic mechanisms of human reproduction. The primary goal is to characterise the intersection of biological reproduction, technological agency, ethical frameworks, scientific knowledge, and public culture through which IVF has become an accepted and regular fact of life. The value of the research lies both in improving sociological understandings of pivotal technological changes in the past, and the improved possibility such understandings off er to the accurate modelling of similar changes in the future, as human reproductive biology is brought under increasingly powerful forms of technological control.

Amount: £992,748
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigation of Mechanisms Linking PIK3R1 Mutations to Metabolic Diseases. 24 Jun 2013

Phosphoinositide 3-kinase (PI3K) is involved in metabolic and mitogenic signalling pathways. Heterozygous autosomal dominant mutations of Class IA PI3K regulatory subunits (PIK3R1), p85alpha, p50alpha and p55alpha, have been identified in patients with SHORT syndrome. This is a rare monogenic disease characterised by a variety of abnormalities including insulin resistance (IR) and hyperglycaemia. Research within the Semple group has focussed on in vitro and in vivo studies of the SHORT mutation Y657X (Y, tyrosine; X, stop codon) of p85alpha. Previous work has not succeeded in deciphering the mechanisms causing the disease phenotype, and this project aims to develop our understanding of how PIK3R1 mutations lead to IR exhibited by patients with SHORT syndrome. It is hypothesised that insulin signalling defects may be facilitated by the shorter splice variants, p50alpha or p55alpha, and that these mutations alter regulation of p110beta-mediated pathways. Additionally, it is proposed that IR occurs in a cell-specific manner from either hepatocytes or adipocytes. Furthermore, PIK3R1 mutations are associated with

Amount: £159,305
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme in Mathematical Genomics and Medicine. 24 Jun 2013

Breast cancer is one of the I eading causes of cancer death in women and is widely considered a heterogeneous disease with very different therapeutic responses and outcomes. Whi le recent advances have I ed to the integration of the genomic and transcriptomic architecture of breast cancers to refine the molecular classification of the disease, the methylation landscape has received less attention. By conducting the largest Next-generation sequencing based breast cancer methylome study, we aim to provide insights into the epigenetic mechanism of tumorigenesis. Furthermore, integrating the methylation landscape with other molecular data such as copy number aberrations (CNA), gene expression and mutations may identify therapeutically tractable signatures and improve classification towards a driver-based taxonomy.The predictive value of the candidate drivers will be investigated in Patient Derived Tumour Xenogra ffts, one of the best pre-clinical models that are able to recapitulate inter- and intratumour he terogeneity observed in patients. Multi-dimensional molecular data and high throughput drug screenings will be integrated to identify novel pharmacogenomics associations.Finally, a portfolio of rele van! molecular signatures will be defined for the purpose of characterisation of circulating tumour DNA. This would enable the possibility of a liquird biopsy for systemic non-invasive monitoring of breast cancer to guide therapeutic stra tegy.

Amount: £159,401
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme in Mathematical Genomics and Medicine. 24 Jun 2013

Spontaneous activity during development has been observed in many parts of the nervous system, and is believed to play an important role in shaping neural connectivity. An efficient method of studying neural activity in vitro is through the use of Multi-Electrode Arrays (MEAs), which allow for the simultaneous recording of the electrica l activity of large networks o f neurons. Our project will use MEA recordings of neural netvvorks from both model organisms and those derived from human stem cells to analyse and model the development of neural activity under normal condi tions, as well as after treatment with various compounds. Our research will involve both computational analysis and theoretical modelling, and has three main goals. Firstly, to analyse the development of spatiotemporal activity patterns in human neural networks, and develop theoretical models to account for the observed experimental behaviour. In particular, we will focus on modelling the mechanisms underlying the emergence of se If-organised criticality in these networks. Secondly, to analyse the effect of inhibitory neurons on the developmental profile of neural networks, through the addition of inhibitory neurons into our theoretical models. And finally, to develop a platform to classify and assess the developmental neurotoxicity of a variety of compounds.

Amount: £159,401
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme in Mathematical Genomics and Medicine. 24 Jun 2013

Haematopoiesis occurs in two distinct waves during development, namely transient primitive haematopoiesis and definitive haematopoiesis that persists into adulthood. Many important questions remain unanswered about the earliest stages of blood development. For example, there are debates on the identity of the ini tial early mesodermal cells that give rise to the H SCs, as well as the factors that regu late the cell fate decisions in these cells. In this project, t seek to provide answers to these questions by utilising recently devel.oped techniques (i.e. single-cell RNAseq [scRNAseq] and single-molecule RNA in situ hybridisation(smRNAISH]) to study haematopoiesis in mouse embryos. Analysis at single cell resolution has the potential to resolve many of the current con troversies on the nature of early blood development. Firstly, I propose to identify subpopulations present in wild type early mesodermal cells using scRNAseq data. Once the sub populations are identified, their spatiotemporal trajectories will be analysed using smRNA ISH . Both scRNAseq and smRNA ISH will then be performed on mutant mice with key transcription factor knockout to observe how the knockouts affect normal haematopoiesis. Finally, I propose to synthesise a transcriptional regulatory network by incorporating all the information obtained from scRNAseq and smRNA ISH .

Amount: £159,401
Funder: The Wellcome Trust
Recipient: University of Cambridge

Function of GPR35 in inflammation 13 Nov 2013

G-protein-coupled-receptors play a major role in inflammation. Pepducins, short peptides coupled with a lipid moiety consciously designed towards the intracellular loops of GPCRs, are a novel approach for modulating GPCRs. They have both, utility for probing GPCR function and for developing novel therapeutics. GPR35, a receptor of unknown function, is activated by kynurenic acid, an end-product of L-tryptophan catabolism and 2-acyl-lysophosphatidic acid. Polymorphisms in GPR35 confer risk for ulcerative colitis and primary sclerosing cholangitis as revealed by genome-wide-association-studies. This proposal intends to address the role of GPR35 in inflammation. It rests on four major pillars: (1) Elucidation of GPR35 signal transduction and downstream biological consequences of receptor ligation. This will include the development GPR35-specific pepducins for the functional study of the receptor, and as novel therapeutics. (2) Interrogation of the role of GPR35 in inflammatory conditi ons in vivo. (3) Investigating the mechanistic consequences of the UC/PSC-associated GPR35 risk variant, through engineered variants, and in cells obtained from individuals with known GPR35 risk allelic status. (4) Investigation whether the pepducin strategy can be extended to pharmacologically correct altered GPCR function arising from genetic variants of GPR35. This may reveal novel precision medicines that target specific genetic variants.

Amount: £630,343
Funder: The Wellcome Trust
Recipient: University of Cambridge