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Currency:
GBP
Recipients:
University of Cambridge
Award Year:
2010

Results

Imaging mechanisms of energy failure following head injury. 07 Oct 2010

Traumatic brain injury (TBI) caused over 170,000 NHS hospital admissions in 2008, requiring over 0.5 million acute hospital bed-days, and over 50,000 intensive care unit bed-days annually. TBI is amongst the most important causes of death in young adults. Survivors experience an enormous burden of physical disability, neurocognitive deficits, and neuropsychiatric sequelae. Despite this, outcome following injury has improved through the provision of protocol driven therapy aimed at preventing an d treating secondary ischaemic insults. However, energy failure may be due to mechanisms other than classical ischaemia, and this may explain the failure of pharmacological neuroprotective therapies. The research detailed in this application aims to improve our understanding of the mechanisms of energy failure following TBI using magnetic resonance imaging, proton spectroscopy and positron emission tomography to map the extent and spatial distribution of metabolic derangements. These will differ entiate classical ischaemia, regional hypoxia secondary to microvascular injury and mitochondrial dysfunction. Sequential measurements of n-acetylaspartate, a mitochondrial metabolite, will address whether metabolic derangements are reversible and represent mitochondrial dysfunction, or irreversible and represent on going neuronal loss. Such data may provide important advances in the development and implementation of successful neuroprotective therapies.

Amount: £184,299
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genome-wide analysis of the interactions that mediate communication between central carbon metabolism and the cellular regulome. 06 Dec 2010

Cells exposed to oxidants re-route their main carbon flow from glycolysis to the pentose phosphate pathway (PPP), by two different mechanisms. One bases on a biochemical block and operates purely on a metabolic level, the other on transcriptional regulation. We found that the two processes compartmentalize over time: After contact with the stressor, the cell induces the metabolic transition in seconds-timescale but it takes minutes until transcripts raise. Remarkably, metabolic changes seem cau sally implicated in regulating this process: induction of the transition activates transcripts of the antioxidant-system. It is the aim of this proposal to identify and analyze regulatory mechanisms which surround the involved metabolic pathways on a genome-scale level. For this, we will develop multiple reaction monitoring (MRM) assays that allow fast quantification of metabolic intermediates, and screen an entire yeast knock-out library composed of 5,200 systematically generated yeast mutants to identify all gene deletions which cause specific changes in the concentration of their intermediates. In a second step, by using a targeted proteomics strategy, these mutants will be screened to identify alterations in the abundance of implicated enzymes. The identified genetic/metabolome interactions are studied for their general importance on metabolism, and analyzed in respect of yeast aging phenotypes.

Amount: £883,906
Funder: The Wellcome Trust
Recipient: University of Cambridge

Non-transcriptional mechanisms of the human circadian clock. 06 Dec 2010

Circadian (or daily) rhythms permeate biology. They are manifest at all levels of biological scale from social activity to cognitive ability - from physiology to self-sustained rhythms in cellular gene expression. It is well established that disruption of our biological clock correlates with impaired performance and increased likelihood of diseased states e.g. metabolic syndrome and obesity. Understanding the intrinsic cellular clock mechanism therefore constitutes an important goal for treatin g human disease as well as increasing workforce productivity. The consensus model for cellular time-keeping posits several inter-linked transcriptional-translational feedback loops at their mechanistic heart. However we have recently observed that human erythrocytes, which lack the capacity for gene expression, exhibit robust rhythms in post-translational modifications associated with cellular redox metabolism. We have also shown this is conserved in murine tissues and algae, and therefore li kely represents an evolutionarily ancient eukaryotic clock mechanism. If funded, this work will likely produce a paradigm shift for many aspects of cell biology with important consequences for understanding the temporal regulation of physiology at a deeper level..

Amount: £854,253
Funder: The Wellcome Trust
Recipient: University of Cambridge

Ultra-Performance Liquid Chromatography Mass Spectrometry for Comprehensive Metabolomics 12 Oct 2010

This application is a request to part fund the upgrade of one of the mass spectrometers used by researchers in Cambridge to conduct open profiling of metabolites, including intact lipids. The requested instrument is a Waters UPLC QToF Xevo which will combine highly reproducible ultra-high pressure chromatography and near exact mass analysis to provide an instrument that will be able to both separate a large number of components and identify these components by a combination of MS and MS^E fragme ntation. The major aims are: 1. To increase sensitivity of the current open profiling LC-MS assays within the Griffin group. This in itself will increase the number of metabolites that can be detected by the instrument, particularly in negative mode where the current Ultima QToF is poor. 2. Allow the use of MS^E and improved software tools for metabolite ID. This will be particularly useful for lipid species where fragmentation produces spectra characteristic of different lipid species. 3. A llow increased use of the instrument by providing a machine that can be used in open access mode for routine LC-MS analysis. Currently one of the biggest bottle necks for collaborators is the availability of experienced users in the Griffin group.

Amount: £177,998
Funder: The Wellcome Trust
Recipient: University of Cambridge

High Resolution Imaging in 3D. 14 Oct 2010

The importance of microscopy in biomedical research cannot be overestimated, because it enables us to visualise the inner workings of the cell. We now know that in order for the cell to function properly, it needs to generate and maintain a number of different membrane compartments. This is achieved by packaging proteins and other molecules into vesicles that traffic from one compartment to another. The Robinson lab is investigating how different membrane proteins are packaged into the right kin ds of vesicles; the Buss lab works on the molecular motors that move the vesicles and organelles around in the cell; the Luzio lab investigates the docking and fusion of vesicles and organelles, in particular lysosomes; and the Griffiths lab focuses on how cytotoxic T lymphocytes (CTLs) orchestrate all their different types of trafficking machinery to kill target cells. Questions we will be addressing using the new microscopes include how different types of vesicles form in space and time, how t he motor protein myosin VI recruits its different partners in living cells, how organelles become tethered to each other prior to fusion, and how the immunological synapses of CTLs are formed.

Amount: £747,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Activation of the endoplasmic reticulum stress sensor IRE1 by lipid perturbations during flavivirus infections. 25 Nov 2010

IRE1 is an endoplasmic reticulum (ER) localized enzyme promoting lipid synthesis and ER membrane expansion. Flaviviruses have been shown to activate IRE1. This project aims to test the contribution of IRE1 activation to flavivirus-induced membrane remodelling and to study the mechanisms of flavivirus-induced IRE1 activation. IRE1 is activated by unfolded proteins accumulating in the ER lumen. However, the recently identified cytoplasmic Q-site of IRE1 which binds to hydrophobic molecules could a lso contribute to flavivirus-induced IRE1 activation. More precisely, virally-induced lipid perturbations could activate IRE1 by a direct stimulation of the cytoplasmic Q-site. To test this hypothesis, we will generate IRE1 mutants that are unable to respond to unfolded proteins or to stimulation through the Q-site. Using IRE1 knock-out cells rescued with the different IRE1 mutants, we will determine to which extent IRE1 activation by unfolded proteins or by stimulation through the Q-site contri bute to flavivirus-induced ER membrane remodelling. Finally, a small compound screen performed in the host laboratory has identified potential IRE1 Q-site ligands. We will test the ability of these molecules to modulate IRE1 activity. Given the heavy reliance of flavivirus replication on lipid metabolism and ER membrane modifications, we will evaluate the antiviral properties of these molecules.

Amount: £606,020
Funder: The Wellcome Trust
Recipient: University of Cambridge

"Leprosy, language and identity in the medieval world" to be held at Cambridge on 5-6 April 2011 14 Dec 2010

This international workshop aims to bring together leading scholars and early career researchers in medieval history, archaeology, palaeopathology, literature and art history to address a multifaceted theme: leprosy, language and identity in the medieval world. The issues of language and identity are central to numerous questions about lepers, leprosy and: leprosaria (leper hospitals) in the Middle Ages, and to broader issues relating to disease from ancient to modern times. There will be ample opportunity for discussion, both formal and: informal, to encourage dialogue between scholars from different disciplines and produce new ideas and conclusions. The: workshop will consist of three 50-minute presentations by keynote speakers (Luke Demaitre, Carole Rawcliffe and Francois-Olivier Touati), approximately ten 20-minute papers, and a roundtable discussion to conclude the second day. The papers will later be published in a volume edited by Elm a Brenner and Peter Murray Jones, marking a much-needed interdisciplinary publication on this topic. The meeting also aims to bring scholars of medieval medicine to the University of Cambridge, where the Department of History & Philosophy of Science is a major centre for the history of medicine. There will be a visit to the Department's Whipple Library on the first day of the workshop.

Amount: £4,520
Funder: The Wellcome Trust
Recipient: University of Cambridge

Physiology: A lexicon history 19 Oct 2010

This project entails a historical synthesis of the expression, physiology. Though this term today denotes a specific biomedical field dealing with the study of how living beings work, it has a much broader scientific heritage. The idiom physiologia originally signified 'discourse on nature' (or 'natural philosophy'- the forerunner of today's expression 'science'). The Greek etymon physis ('nature') has generated one of the most diverse arrays of word-forms in the history of science. It is the origin of such latter-day words as 'physics' and 'physician', as well as 'physiology'. How, why, and when these terms split from their mutual etymological ancestor- and, more specifically, how the erstwhile universal name 'physiology' acquired its home in biomedicine- are questions explored in this project. While the birth right of physiologia is well known to scholars of the ancient world, it is not familiar to today's practitioners of the biomedical sciences. The proposed study will interweave a number of timely etymologic and semantic historical threads, coming to the fore recently, that bear upon the modern-day field of physiology. The work will culminate in a monograph, representing a popular account aimed at the interface between the history of science and contemporary biomedicine, particularly today's Physiome Project.

Amount: £4,600
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of neural crest cells in olfactory/terminal nerve and GnRH neuron development. 05 May 2010

Throughout life, olfactory ensheathing cells (OECs) promote axon-sprouting from olfactory-receptor neurons (ORNs) and guide them to their targets in the olfactory bulbs. These properties mean OECs are intensively studied as therapeutic agents for transplant-mediated spinal cord repair, but how they act to promote functional recovery remains unclear. Mounting evidence suggests OECs also promote entry into the embryonic forebrain of olfactory/terminal-nerve axons and gonadotropin-releasing-hormone neurons: failure of these events causes anosmia and sterility (Kallmann s syndrome; KS). We have recently found that OECs are derived from the neural crest, and not from the olfactory placodes as current dogma holds. This opens up new possibilities for elucidating the mechanisms underlying the interactions of OECs with axons and other cells. By analysing mutant mouse embryos, and using recently-developed conditional in ovo electroporation techniques, we will (1) investigate the requirement for OECs for olfactory/terminal axon and GnRH neuron entry into the forebrain; (2) test hypotheses about three potential underlying molecular mechanisms: FGF signalling, matrix-metalloprotease secretion and Wnt signalling. A better understanding of the molecular basis of OEC interactions with other cells and axons should shed new light on KS, and potentially also on the mechanisms by which OECs promote spinal cord repair.

Amount: £225,147
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Fragments of Asclepiades of Bithynia. 24 Mar 2010

The proposed project will provide the essential scholarly foundation for answering the research questions asked, namely a critical edition of all the fragments and testimonia relating to Asclepiades of Bithynia and the subsequent members of his medical sect, a collection which has long been recognized as an urgent desideratum (e.g. by van der Eijk (2001), 6; Rawson (1982), 370; Schrijvers (1976), 253 n. 35). The edited fragments will be accompanied by translation and full exegesis, in the form o f both interpretative, contextualizing essays and line-by-line commentary. Heinrich von Staden s Herophilus: The Art of Medicine in Early Alexandria (Cambridge 1989) is at present conceived of as the closest model for the projected publication. At this early stage, it is envisaged that the fragments will be arranged under seven general headings, each to be accompanied by an interpretative essay: (1) Life and Works; (2) Theory of Matter; (3) Epistemology, Theory of Sensation, Psychology; (4) Phys iology; (5) Pathology; (6) Therapeutics; (7) The Asclepiadean Sect. This will also constitute the first comprehensive study of Asclepiades life and thought, the development of his medical sect, and the long-term significance of his theories.

Amount: £136,764
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structural and functional studies of regulatory assemblies and macromolecular machines. 19 Apr 2010

Many macromolecules in the cell function through multi-component assemblies whose activities can affect complex processes. We propose to study representative assemblies that play central roles in the regulation of gene expression and the coupling of metabolic pathways, and that comprise the machinery of transmembrane transport: Gene expression. Orchestrated turnover of mRNA is a key determinant of gene regulation. A critical role in regulating the balance and composition of mRNA transcripts is played by the multi-component RNA degradosome in Escherichia coli, effecting the coordinated expression of many genes from diverse metabolic pathways. We have solved several structures of the degradosome components and are investigating their interactions. We will study the structure and function of the complete assembly and of the analogous exosome, to explore how the machinery has evolved to meet the requirements of an expanded genome. Metabolism. We are continuing to investigate multi-enzyme systems, such as 2-oxoacid dehydrogenase, building on our structure determination of a subassembly and identification of a new mechanism of intersubunit-communication. Transport. We are investigating the movement of drugs and proteins across biological membranes. We will continue studies of a variety of energy-driven transporters, their assembly and mechanism, based upon our crystal structures.

Amount: £342,635
Funder: The Wellcome Trust
Recipient: University of Cambridge

Ribosomal frameshifting and readthrough in virus gene expression. 24 May 2010

This project will focus on the role of recoding in the replication of the model retroviruses Rous sarcoma virus (RSV; frameshifting) and murine leukemia virus (MuLV; readthrough) and the coronavirus murine hepatitis virus (MHV, frameshifting). Specific mutations will be introduced into the recoding signals such that individual viruses, over a broad range, exhibit a defined frameshifting or readthrough efficiency. The replication of these engineered viruses will be assessed and their tolerance to changes in efficiency determined. As an alternative approach, recoding efficiency will be modulated using small molecules, including antibiotics known to affect recoding, and by targeting the stimulatory RNA structures with oligonucleotides. The mechanism of the readthrough process will also be investigated. Unlike frameshifting, we know little about how the stimulatory RNA pseudoknot of MuLV perturbs ribosome function. This will be investigated by biochemical analysis of ribosome-pseudoknot co mplexes, using primer-extension/toeprinting, RNA secondary structure probing and cryo-electron microscopy (cryo-EM).Overall, this project aims to establish the extent to which recoding can be modified before virus replication is compromised, to determine whether recoding is a valid target for antiviral intervention and to clarify the mechanism of readthrough, which may identify new approaches to antiviral therapy.

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

"A programme of events by Mary Fissell in Cambridge" to be held in Cambridge form January to July 2011 13 Jul 2010

We seek support to bring Professor Mary Fissell to Cambridge to strengthen and enhance our programme on 'Generation to Reproduction', the core activities of which are supported by a Strategic Award (2009-14).

Amount: £3,900
Funder: The Wellcome Trust
Recipient: University of Cambridge

Diabetes and Inflammation Laboratory. 12 Apr 2010

The DIL has helped identify over 40 regions of the genome that influence risk of type 1 diabetes. In each of these chromosome regions are DNA variants that alter the expression and function of genes and increase or decrease predisposition to the autoimmunity and pancreatic beta-cell destruction that causes the disease in most cases. By more detailed genetic mapping and by correlating polymorphism with alterations gene expression, splicing, protein product activity and perturbation of non-protei n coding RNAs, causal genes and their phenotypes will be identified. The effects of the major causal pathways will be modelled in vivo.

Amount: £8,280,487
Funder: The Wellcome Trust
Recipient: University of Cambridge

Value in People Award. 29 Mar 2010

Not available

Amount: £350,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentship supplements 13 Apr 2010

The new Institute for Stem Cell Biology in Cambridge will be an international centre of excellence in fundamental stem cell research. The Institute will focus on definition of the genetic and biochemical mechanisms that control stem cell fate, providing foundations for applications in disease modelling, drug discovery and regenerative medicine. This proposal is for provision of core resources for embryonic stem cell manipulation and transgenesis. A central resource of skilled personnel will maximise research productivity and continuity, promote cooperation and synergy, and accelerate technological innovation. Timely and efficient production of customised gene-modified stem cells and mice is essential underpinning. Specialised expertise will support advanced genetic engineering of mouse and human stem cells, and operation of robotic platforms to develop screening methodologies for isolating genetic, protein and chemical regulators. A dedicated PdD programme in stem cell biology will capitalise on the opportunity for high level research training provided by the intellectual environment and core facilities in the Institute. A Strategic Award will immediately establish the Institute for Stem Cell Biology amongst the best-resourced and most attractive environments for stem cell research world-wide, providing a magnet for recruitment, and a much-needed focus for UK and European stem cell biology.

Amount: £93,059
Funder: The Wellcome Trust
Recipient: University of Cambridge

Maths and Health: multimedia resource packs for schools linking the biomedical sciences to the Key Stage 3/4 mathematics curriculum 14 Apr 2010

The project will produce high-quality, topical multimedia resource packs aimed at Key Stage 3/4 school students and their teachers, providing stimulating, engaging material that demonstrates the application of specific mathematical topics in real-world biomedical contexts. This project will support learning about the biomedical sciences through introducing them into the mathematics classroom, encouraging school audiences to engage with the biomedical sciences from a new perspective. The project also aims to make direct links between the Key Stage 3 and 4 mathematics curriculum and the biomedical sciences, encouraging interdisciplinary and cross-curricular work. The multimedia resource packs will provide explanatory materials and resources, including video clips, Powerpoint presentations and teacher guidance notes, introducing biomedical science topics at a level appropriate for a KS3/4 audience and designed for use within the constraints of a timetabled mathematics lesson. The resources will include activities designed to engage pupils in collaborative investigative and problem-solving tasks, and to encourage discussion and debate. Pupils will be encouraged to think about the methodologies of applying mathematics to real-life situations, and consider and debate some of the ethical and social issues that may arise in these contexts. The project will help KS3 and 4 students to develop a more critical and informed understanding of the mathematical basis ? e.g. probability, or the use and presentation of statistics ? underlying information on medicine, healthcare and the biomedical sciences. Through investigative projects in which pupils must apply their mathematical skills within biomedical contexts, the project aims to increase students? mathematical abilities, confidence and transferable skills.

Amount: £29,845
Funder: The Wellcome Trust
Recipient: University of Cambridge

Infection and Immunity 13 Jul 2010

The mechanism of the T cell receptor (TCR) triggering, leading from the biding of its ligand (an agonist peptide complexed with a Major Histocompatibility Complex [agonist pMHC]) to the transduction of the signal across the plasma membrane, is an object of controversy. Three main non-exclusive models have been proposed: aggregation, conformational change and segregation1. Our aims are to answer the following fundamental questions: 1. What is the natural state of the TCR at the membrane of a resting T cell? 2. What is the main mechanism responsible for the earliest molecular events of TCR triggering? 3. How are microclusters of TCR formed after contact with an antigen presenting cell (APC), before the formation of the immunological synapse (IS)?

Amount: £152,290
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of plasmalogenphospholipids in obesity and insulin resistance. 15 Feb 2010

General aims: To investigate the pathogenic role of plasmalogen depletion in the development o he Metabolic Syndrome. Soecific aims: 1) To elucidate the effect of plasmalogen depletion on energy balance, lipid and carbohydrate metabolism. 2) To characterise the metabolic effects of tissue specific plasmalogen depletion in key metabolic organs such as adipose tissue. 3) To determine the therapeutic value of replenishing plasmalogens in models of obesity and insulin resistance. ' 4) To identify the metabolic pathways altered in the context of plasmalogen depletion using a systems biology approach.

Amount: £53,487
Funder: The Wellcome Trust
Recipient: University of Cambridge