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Recipients:
University of Cambridge

Results

Translational Medicine and Therapeutics Programme at the University of Cambridge: 'The apelin-ACE-2 axis in cardiopulmonary disease'. 31 Aug 2011

The objective of the project is to test the hypothesis that apelin signalling is altered in PAH and that apelin may be a new mediator and potential new drug target for this condition. Basic and translational research into the pharmacological actions of apelin has been hampered by a lack of selective agonists and antagonists. Two novel molecules have recently been discovered by the group: MM07 an agonist and MM54, a competitive antagonist at the apelin receptor (APJ). This project will focus on identifying the cellular expression of apelin and APJ and measuring APJ densities and pharmacological characteristics in lung and right ventricle from patients with PAH to determine changes in the apelin/APJ system in this disease. Parallel studies will be carried out in heart and lung of the monocrotaline-treated rat to discover if this model reflects the changes in the apelin system in human tissues. I will determine the effects of MM07 and MM54 on progression of PAH in this animal model to identify whether pathway stimulation or blockade improve outcome. In collaboration with Dr I Wilkinson, I plan to perform forearm plethysmography in healthy subjects. If successful, it would be possible, subject to ethics approval, to perform limited studies in PAH patients.

Amount: £268,427
Funder: The Wellcome Trust
Recipient: University of Cambridge

Training Programme in Translational Medicine and Therapeutics at the University of Cambridge: 'Comprehensive analysis of structural rearrangements in the progression from Barrett's oesophagus to oesophageal adenocarcinoma.' 30 Nov 2010

Oesophageal adenocarcinoma has a dismal prognosis; median survival is <1 year. It is thought that chromosomal rearrangements (including inversions, translocations, deletions and insertions) may play as much of a role in the development of cancer as the more thoroughly studied point mutations. Paired-end Sequencing allows rapid analysis of virtually all breakpoints in a tumour to a resolution of 500bp. Simultaneously it provides highly accurate copy number data comparable to that from arrayCGH. The Barrett's-?Dysplasia-?OAC is a well recognised paradigm. Ease of accessibility and longitudinal sampling as part of standard clinical practice provides a unique opportunity to study the biology of progression in epithelial carcinoma. Key Goals 1. Investigate structural rearrangements and copy number abnormalities involved in the genesis of oesophageal carcinoma in a small group of carefully selected patients with samples representing Barrett's oesophagus, Oesophageal adenocarcinoma and normal tissue from the same patient. 2. Confirm the importance of individual structural rearrangements by screening a large collection of primary tissue samples and comparison with clinical outcome 3. Functional assessment of potential therapeutic targets 4. Investigate the potential of personalised assays, based on unique structural rearrangements, for tumour cell-free DNA in patient serum as markers of disease status

Amount: £97,095
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Casebooks Project: Simon Forman and Richard Napier's Medical Records, 1596-1634. 12 Nov 2009

The project s primary goal is to produce an electronic edition of Forman and Napier s casebooks. This will contain roughly a million words of transcribed text, plus an extensive editorial apparatus. Users will be able to view the records either as facsimile transcriptions or to interrogate them, generating tables of associated cases. The edition will be mounted on an open-access website which will include: a scholarly introduction, as one would expect of a critical edition; more accessible mater ial introducing the casebooks and Renaissance astrology and medicine; instructions for using the edition for scholarly and pedagogic purposes; and full technical documentation. The project s second major objective is to use the edition of Forman and Napier s casebooks to initiate collective reflections amongst historians of medicine about patients and medical records. Scholars will be brought together in two workshops. The first will introduce the edition, consider the current state o f work in the field, and establish essay topics for an edited volume on the patient in history. Draft essays will be circulated and discussed at the second workshop. The resulting volume will present cutting edge research on the patient in history and set the standard in the field for future scholars.

Amount: £398,817
Funder: The Wellcome Trust
Recipient: University of Cambridge

Glycosphingolipid catabolism and transfer in health, disease and immunity. 13 Jul 2010

1) To investigate the molecular mechanism of lipid binding and solubilisation by saposin molecules. 2) To reveal the molecular mechanism by which saposins A and C present substrate and activate GalC. 3) To fully investigate the consequences of known clinical mutations on GalC stability, activity, cellular location/trafficking and interaction with substrate, membranes and saposins. Can these parameters be affected in vitro and in vivo by inhibitor or chaperone binding? (In collaboration with Prof. Paul Luzio) 4) To reveal the molecular mechanism by which saposins load lipid antigens onto CD1d and CD1b molecules. To test the hypothesis that saposins mediate loading of specific myelin-related autoantigens, and determine whether autoreactive T cells or NKT cells exist in patients with Krabbe disease and Multiple Sclerosis (In collaboration with Prof. Timothy Cox).

Amount: £152,290
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 myocardin in vascular smooth muscle cell inflammatory activation and disease. 18 Jan 2010

I) To expand upon preliminary observations that myocardin overexpression can suppress interleukin (IL)-113-induced IL-6-release in rat VSMC cell culture, by assessing the ability of myocardin to regulate multiple inflammatory pathways in VSMCs in vitro. 2) To elucidate mechanisms ofmyocardin action, focussing initially on possible NF-KB, C/EBP and micro-RNA mediated mechanisms. 3) To assess the effect of both reduced and elevated VSMC myocardin levels on atherosclerotic plaque development, inflammation and progression in vivo using mouse models.

Amount: £29,414
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of c-myc in cardiac hypertrophy and heart failure. 15 Feb 2010

The aim of this project is to clarify the role of c-myc in heart failure by achieving the following objectives; 1. Detailed examination of the expression of c-myc human heart failure 2. ChiP-seq analysis of c-myc bound DNA loci in control and end stage dilated human cardiomyopathic hearts 3. Examination of c-myc expression in animal models of fibrosis and . heart failure in association with analysis of angiogenesis, apoptosis, extra-cellular matrix remodelling and DNA damage 4. Assessment of DNA damage, protection or susceptibility to fibrosis and dilatation in a cmyc expression and induction in a myocyte specific inducible transgenic c-myc overexpressing mouse model The expected beneficial outcomes of this project are i) clarity on the expression and level at which expression of c-myc is regulated through the dynamic process of heart failure, ii) identification of genomic localization of c-myc and the mechanisms by which c-myc regulates cardiac gene expression and iii) the role of c-myc in the regulation or deregulation of features of heart failure including DNA damage and fibrosis. These outcomes will allow for future work to examine how mechanisms in c-myc-related pathways may be targeted for novel heart failure therapy, and to improve the basic understanding of molecular biology of both heart failure and c-myc-DNA interactions.

Amount: £14,309
Funder: The Wellcome Trust
Recipient: University of Cambridge

Transgenic animals: Genetically modified mice in Britain and the United States, 1970-2000 10 Jun 2010

To explore the history of GM mice, I will begin by studying technical innovations in mammalian embryology and reproductive physiology in the 1970s. In particular, I will consider how the techniques travelled, through multiple exchanges between laboratories in Britain and the US, and how this research was variously combined with recombinant DNA technologies developed in the 1970s to produce multiple transgenic mice in 1980-1. Then I will explore the parallel lines of research on embryonic carcinoma (EC) and embryonic stem (ES) cells in the 1970s and 1980s. To assess the effect of the new kinds of animals on the infrastructure of their breeding and supply, and the stabilisation of their production, I will use as a case study the MRC Radiobiology Unit (Mammalian Genetics Unit since 1995) in Harwell, a stock centre and research facility for mouse experimentation, in the 1980-1990s. I will pay special attention to criteria for genetic modification and negotiations over the status of the mice. Finally, to analyse the (contested) use of GM mice as models of human disease, I will consider the induction of breast cancer through oncogene insertion.

Amount: £85,708
Funder: The Wellcome Trust
Recipient: University of Cambridge

Clinical PhD Programme at the University of Cambridge: 'Functional characterisation of responses to DNA damage in human cells.' 21 Sep 2010

Failure of accurate DNA damage sensing and repairing mechanisms manifest as a variety of human diseases including cancer. Cytotoxic chemotherapy and radiotherapy remain the most beneficial in terms of cancer treatments and largely act through the generation of DNA damage. Accuracy and efficiency of DNA damage detection and repair requires the recruitment and subsequent post-translational modification of various proteins. Ubiquitylation and sumoylation are highly dynamic and reversible enzymatic processes that play crucial roles during the execution of DNA damage sensing and repair. Further characterization of the enzymes involved in these processes is required in order to fully understand how the DNA damage response (DDR) is regulated and has the potential to provide new therapeutic targets. PIAS SUMO E3 ligase enzymes are necessary for human cells to respond appropriately to and effectively repair DNA double-strand breaks. ZIMP7 and ZIMP10 are two PIAS -like proteins that also contain a SP-RING/Miz zinc finger domain that potentially confers E3 ligase activity. Very little previous research has been focused on these proteins. I have demonstrated that both ZIMP7 and ZIMP10 are recruited to sites of DNA damage induced by laser micro-irradiation in cultured human cell lines. My goal now is to characterize the precise functions of ZIMP7 and ZIMP10 in the DDR.

Amount: £221,618
Funder: The Wellcome Trust
Recipient: University of Cambridge

Clinical PhD Programme at the University of Cambridge: 'Early life immune and metabolic function and psychotic symptoms in the ALSPAC birth cohort.' 21 Sep 2010

Schizophrenia is associated with proinflammatory changes (increased cytokines in serum and CSF). Recent evidence suggests important effects of hormone leptin on immune system and cognition. Cognitive dysfunction is also prominent in patients with schizophrenia. However, prospective studies are required to establish importance of inflammatory cytokines and their modulators, such as leptin in the pathophysiology of schizophrenia. Increased risk of schizophrenia is also observed among individuals exposed to immune activation or infection during early life. There is evidence, inflammatory cytokines can increase fetal exposure to maternal glucocorticoids leading to long term changes in hypothalamic-pituitary-adrenal (HPA) axis functioning. Alterations of HPA axis functioning by early life environmental factors may be a common link between chronic diseases of adult life, such as hypertension, type 2 diabetes and schizophrenia. Besides, schizophrenia is associated with subtle alterations in motor and cognitive development early in life. Early environmental factors such as immune activation may interfere with neurodevelopment, and thus contribute to disease risk. However, effects of early life immune dysfunction on human neurodevelopment are yet to be explored. We propose a study of early life (pre and post natal) immune activation and risk of psychotic symptoms, and motor and neurocognitive development in ALCPAC birth cohort.

Amount: £224,505
Funder: The Wellcome Trust
Recipient: University of Cambridge

Statistical methods for the study of molecular mechanisms of disease 14 Jun 2010

Genome-wide association (GWA) studies have been very successful in pointing to genetic loci associated with risk of type 1 diabetes (T1D) and other diseases. We knew only two or three such loci for T1D when I took up my fellowship at the end of 2000 while now we have 45. The pace at which new data has been generated in the last two to three years has been such that some analysis remains to be done on existing datasets. Examples include pathway?based analyses and meta-analysis of results for multiple autoimmune diseases. But GWA studies cannot identify all disease susceptibility loci. In particular, low frequency variants with larger effects are certain to occur and may prove more valuable for further study of disease mechanisms. Advances in high-throughput sequencing and genotyping arrays promise to allow us to extend the spectrum of frequency and types of disease variants which we can identify. But statistical problems will be faced in the design and analysis of such studies. I would hope to contribute to the solution of these problems.

Amount: £307,306
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Road from Pluripotency to Lineage Determination. 22 Apr 2010

Pluripotency is the capacity of individual cells to initiate all lineages of the mature organism in response to signals from the embryo or cell culture environment. Pluripotency has no predetermined programme; it is a tabula rasa. This is the foundation of mammalian development and of embryonic stem (ES) cell biology. Genetic and cell biological studies point to transcription factor command rather than epigenetic governance of the pluripotent state. Persuasive support for this view comes from th e demonstration that pluripotency can be recreated from somatic cells through transcription factor induced reprogramming. We now wish to investigate the other side of this coin; how pluripotent cells exit from a naive ground state and become committed to different lineages. Our hypothesis is that fibroblast growth factor stimulation of the mitogen activated protein kinase cascade perturbs the ground state and creates a metastable condition in which cells are poised for multilineage commitment. W e aim to isolate cells in this transition state and interrogate their regulatory circuitry at both population and single cell levels using quantitative transcriptomics, proteomics and biochemistry, complemented by genetic manipulation and live cell tracking. Through these studies we hope to deepen understanding of the underlying design principles of pluripotency lineage choice.

Amount: £1,736,222
Funder: The Wellcome Trust
Recipient: University of Cambridge

Pharmaceutical ethics beyond distributive justice. 18 Jan 2010

The aims and objectives of this project are threefold. Firstly, it aims to convey the conclusions of my current WT-funded research on Needs, Rights, and Preferences in Pharmaceutical Ethics to key stakeholders in healthcare, including policy makers. Secondly, it seeks to inform policy and practice and to stimulate further discussion. Thirdly, it pertains to a broader project of both reengaging academic philosophy with timely social concerns and making philosophical arguments accessible to wide r audiences. The project involves two stages: 1. preparing and disseminating outreach materials, e.g. a concise summary of key arguments, terminology guides, and annotated bibliographies; and 2. organising and running a series of approximately 8 seminars and two half-day workshops for relevant non-academic audiences both at Cambridge University and on the premises of interested organisations. These dissemination activities will draw on the outputs of my current research on the philosophic al presuppositions that underlie conflicting distributive claims in pharmaceutical ethics. The proposed methodology is Socratic engagement. It helps participants expand their own critical reflection and does not require prior knowledge of philosophical terminology. The anticipated impact is to further pertinent policy and practice, philosophically inform key healthcare stakeholders, and encourage further debate within the larger community.

Amount: £29,908
Funder: The Wellcome Trust
Recipient: University of Cambridge

The molecular biology of rotavirus assembly. 08 Jul 2010

In the last two and a half years we have been studying rotaviruses (RV). We have identified potentially important RNA structures controlling aspects of RNA replication and have made the surprising discovery that RV use lipid droplets (LD)as virus factories (viroplasms) within cells. Disruption of LDs with drugs inhibits RV replication. We are planning a coherent series of studies to build on this. We will study the RV/LD interaction in detail with siRNA knockdown of LD components, lipid analysi s and immunoprecipitations to investigate the virus LD interaction further. We will continue seeking and further characterising RNA structures in the RV segments to find and elucidate the functional role of these in RV replication and genome packaging. We will continue our programme of establishing a plasmid only-based reverse genetics system for RV building on the success we have had so far in isolating and expressing individual RNA segments from RV. These latter two studies will allow us to id entify packaging signals for RV genomic segments.

Amount: £204,611
Funder: The Wellcome Trust
Recipient: University of Cambridge

Foetal testosterone effects on brain development. 01 Jul 2010

In this application we test if foetal testosterone (fT) (produced at significantly higher levels in males) exerts organisational effects on human brain development. Whilst fT has been demonstrated to exert organisational effects on brain development in other animals, this hypothesis has never been directly tested in humans. We have conducted a unique study where we measured fT prenatally in amniotic fluid and followed the children from birth to predict behavioural development longitudinally. Our research thus far has shown that fT is a key predictor of various social and communicative behaviours. We now have a valuable opportunity to employ neuroimaging with this sample to examine the underlying effects of fT on brain development. Our primary aims are: (1) To test if foetal testosterone (fT) and/or current testosterone (cT) correlate with volume of the whole brain and/or with volume of specific sexually-dimorphic brain regions, using structural MRI. (2) To test if fT and/or cT co rrelate with brain activity in these sexually-dimorphic brain regions, during social-emotional processing using functional MRI. (3) To test if fT and/or cT correlate with measures of neuroanatomical connectivity using diffusion tensor imaging (DTI).

Amount: £289,602
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

TRC8, a novel ERAD ubiquitin E3 ligase in the regulation of MHC class I and other substrates. 08 Feb 2010

We will characterize the role of TRC8, a novel ERAD E3 ligase. Our recent identification of TRC8 as the E3 required for the US2-mediated dislocation of MHC I implies a role for TRC8 in the ERAD pathway. We showed TRC8 associates with signal peptide peptidase (SPP) and these enzymes form the core components of a novel ERAD complex. Together with the observations that loss of TRC8 leads to the development of renal tumours, our findings show TRC8 is an important human ERAD ligase which requires fu rther investigation. Our characterization of TRC8 will determine the functional requirement for the TRC8 sterol sensing domain, identify additional cellular components of the TRC8/SPP complex and determine whether SPP s protease activity is essential for protein dislocation. Preliminary data from mass spectrometry analysis identified the multifunctional FKBP38 protein as a new TRC8 substrate. FKBP38 regulates the PHD2 oxygen sensor, and we will therefore determine whether TRC8 regulation of FKBP 38 affects PHD2 stability, activity of the hypoxia-inducible transcription factor (HIF) and explains how loss of TRC8 causes renal cancer. Additional TRC8 substrates will be identified using SILAC-based quantitative mass spectrometry from different cell types. These studies will provide insight into the functions of this clinically important ligase.

Amount: £205,398
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

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

Biomedical Vacation Scholarship 24 Jun 2013

Not available

Amount: £19,620
Funder: The Wellcome Trust
Recipient: University of Cambridge