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Award Year:
2016
Currency:
GBP
Recipients:
University of Cambridge

Results

Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia 06 Dec 2016

Secondary pneumonia following influenza infection is common, with considerable associated morbidity and mortality. Strikingly, secondary infections tend to arise from bacteria which live otherwise asymptomatically in the oropharynx. Based on existing data, I hypothesise that the development of secondary streptococcal pneumonia is dependent on a key immune-cell molecular pathway, namely Phosphoinsitol-3-Kinase delta (PI3Kdelta), and that inhibition PI3Kdelta will be protective via the following mechanisms. 1) Influenza-induced expansion of immunosuppressive regulatory T-cells (Treg) which depend on PI3Kdelta for suppressive functioning 2) Viral and Treg mediated suppression of neutrophil function 3) A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by Streptococcus pneumoniae. The goals are: 1) To determin whether PI3Kdelta-null animals are resistant to secondary streptococcal pneumonia. 2) To use tools including Treg depleted animals, conditional knockout animals and small molecule PI3Kdelta inhibitors to explore mechanisms of resistance. 3) To develop a more clinically relevant murine model secondary pneumonia, using a streptococcal colonisation model which when exposed to influenza will develop secondary pneumonia. 4) To characterise the respiratory microbiome of animals at various stages will be characterised, looking for factors that may facilitate or militate against development of secondary pneumonia.

Amount: £516,560
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neuronal reward mechanisms 30 Nov 2016

We investigate neuronal reward and economic decision signals in behavioural tasks with designs from learning and economic decision theories, supplemented by selected, closely related neuroimaging experiments. We study the main components of the brain's reward system, including dopamine neurons (reward prediction error), orbitofrontal cortex (economic decision variables), striatum (so far insufficiently characterised reward signals) and amygdala (short- and long-term rewards). We search for reward and decision signals that provide explanations and hardware implementations for the constructs of reward and economic theories. We need to know these fundamental neuronal signals before focussing on cellular and molecular mechanisms, which differs from work on sensory and motor systems whose signals are better characterised.  We state three aims:  Aim 1: We characterise neuronal processing of skewness-risk, arguably the most frequent risk form.  Aim 2: We identify neuronal signals for utility and test formal axioms for utility maximisation, which is supposedly the goal of 'rational' agents. Utility is THE basic economic decision variable that explains most economic choices.  Aim 3: We assess neuronal representations of preferences, and bridge the gap between biologically necessary rewards and tradable economic goods, by testing basic assumptions of revealed preference theory.

Amount: £4,413,529
Funder: The Wellcome Trust
Recipient: University of Cambridge

Genetics and causality: towards more accessible and more reliable Mendelian randomization investigations 26 Oct 2016

I propose to advance methods for Mendelian randomization to make investigations more reliable and more accessible, and to build a team to develop and apply these state-of-the-art methods. I will continue with the development of robust methods that give consistent estimates even when the stringent instrumental variable assumptions are not fully satisfied, and compare how these methods perform with real data. I will extend existing methods, considering estimates of non-linear causal relationships, and approaches for variable selection with heterogeneous genetic variants in different gene regions, and with highly-correlated variants from the same gene region. I will develop novel approaches for using covariate matching and matching by design (such as the analysis of sibling pairs). I will disseminate these methods in explanatory papers aimed at applied researches, and in a software package. I will partner with leading epidemiological and clinical researchers to apply these methods to scientific questions of interest, and feedback difficulties from these analyses into further methods development. I will develop pipelines for the prioritization of biomarkers as targets for pharmaceutical or clinical intervention from high-dimensional datasets, where thousands of candidate risk factors have been measured and detailed analysis of each risk factor in turn is impractical.

Amount: £724,155
Funder: The Wellcome Trust
Recipient: University of Cambridge

Evaluation of feasibility of assessing liver function during ex situ liver perfusion using microdialysis 01 Apr 2016

Each year 15% of patients on the UK liver transplant waiting list die awaiting a donor liver, while a significant proportion of livers go unused because clinicians are unsure that the liver would provide life sustaining function. We are now able to perfuse a liver ex situ with oxygenated blood while evaluating markers of damage and function, enabling better assessment of organ viability. Microdialysis is a method in routine use in neurosurgery to evaluate brain metabolism following trauma, and involves passing a fine dialysis catheter into the brain parenchyma and perfusing it with an isotonic perfusate and examining the dialysate for metabolic markers such as glucose, lactate, and pyruvate. It can also be used to interrogate metabolism by introducing labeled substrates. Microdialysis has been used to study liver transplants post transplant, but has not been used to evaluate function ex situ where its relatively rapid readout may facilitate early and accurate decision making.This project will examine the feasibility of using microdialysis in perfused livers. Human livers that have been declined for transplantation will be studied and the optimal technique developed. Microdialysis results will be correlated with perfusate chemistry (lactate fall, maintenance of pH, ALT, AST) and metabolomic profile.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Development of an In Situ Treatment Method for Twentieth Century Moisture Damaged Paper 18 May 2016

This project will undertake the conservation and long-term preservation of a moisture-damaged Nominal Roll from a Second World War civilian internment camp at Changi, Singapore. The Nominal Roll is a unique historical document of international significance, recording the personal information of individual internees, who were drawn from over twenty different countries. It is currently being conserved at Cambridge University Library as part of a digitisation project funded by the Wellcome Trust, but preliminary work indicates that further research is essential to determine the best course of conservation treatment. Examination and assessment of a range of treatment methods will be carried out using specialist investigative imaging equipment, which will be acquired for the project. The development of a successful treatment will not only ensure the long term survival of the Nominal Roll, but will also inform the conservation of significant collections of similarly damaged twentieth-century material within the Library’s collections and the wider archival community.

Amount: £20,097
Funder: The Wellcome Trust
Recipient: University of Cambridge

Does Epicardium promote Cardiomyocyte Maturation & Cardiac Regeneration? 29 Jun 2016

Human embryonic stem cells (hESC)-derived cardiomyocytes have great potential for cardiac repair and regeneration following myocardial infarction but remain significantly challenged by graft cell survival, maturation and vascularisation. The epicardium is essential for cardiac development as it forms cardiac fibroblasts, coronary smooth muscle cells, and controversially, cardiomyocytes and endothelial cells. The epicardium has emerged as a potential cardiovascular progenitor source for vascularization and cardiomyocyte support. Signalling pathways underpinning epicardial-myocardial cross-talk are postulated to be key in cardiomyocyte maturation and regeneration. Studies based on mouse models have identified several epicardium-derived paracrine factors that increase the number of cardiomyocytes and contribute to angiogenesis, although their role in cardiac maturation is unclear. This project aims to definitively characterize the role of epicardium in promoting cardiomyocyte maturation and regeneration. Key goals are: 1) To investigate the role of hESC-derived epicardial cells in the promotion of functional integration and maturation of cardiomyocytes in an in vitro tissue-engineered cardiac construct. 2) To interrogate the role of paracrine mediators including MDK and/or FSTL1 in promoting cardiomyocyte maturation and regeneration. 3) To investigate the function of hESC-derived EPDCs in promoting the survival, maturation, electrical connectivity and function of stem cell-derived cardiomyocytes in the mammalian myocardial infarct.

Amount: £270,886
Funder: The Wellcome Trust
Recipient: University of Cambridge

The genetics of the Drosophila mitochondrial DNA and its influence on evolution and diesease 01 Jun 2016

The multicopied mitochondrial genome makes major contributions to life, disease and aging, but the rules governing its transmission, segregation and selection from one generation to the next are still largely unknown. These rules not only determine the evolution of the genome, but also influence the progression of mitochondrial disease and aging in somatic tissues. In the past, I have developed novel genetic tools in Drosophila to probe the poorly understood mitochondrial genetics. Interesting, I showed that detrimental mitochondrial mutants are selectively prevented from transmitting to offspring during oogenesis (i.e. purifying selection based on function). On the other hand, when diverged genomes from different species were paired, a selfish selection that promotes gains in transmission of mitochondrial genomes without regard to impact on function of host was observed. Here, I propose to apply genetic, cellular and biochemical tools to reveal the biological bases of the two selections and identify nuclear genes controlling mitochondrial genome competition. Meanwhile, I will reveal how mitochondrial genetic variations affect broad-scale organismal phenotypes such as longevity and fertility. These studies will significantly advance our understanding of rules governing transmission of mitochondrial genomes, provide new insights into mitochondrial-related diseases and generate new ideas for treatment options.

Amount: £1,153,380
Funder: The Wellcome Trust
Recipient: University of Cambridge

Functional characterisation of the human virome through expression screens in human cells 19 Apr 2016

Viruses manipulate the machinery of their host cell to permit their efficient replication whilst simultaneously evading detection by the host immune system. Deciphering the mechanisms by which viral genes achieve these goals, therefore, is informative not only for understanding the mechanisms of viral pathogenesis, but also for elucidating the basic biology of the cell. However, no large-scale approach is currently available to identify viral genes that modulate a particular cellular pathway. I will overcome this limitation by creating a large-scale plasmid library of viral genes, which will be introduced into human cells to carry out expression screens. My primary goal is to use this approach to identify novel viral genes that antagonise the sensing of viral nucleic acids, using fluorescence-activating cell sorting (FACS) to isolate cells that - as a result of expressing a single viral gene - can no longer mount an interferon response to transfected DNA or RNA. Overall this work will 1) reveal new insights into the mechanisms by which cells respond to viral nucleic acids, and 2) develop a method that will be broadly applicable to enable the identification of viral genes that modulate theoretically any cellular process important for viral replication or immune evasion.

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

Role of epigenetic mechanisms in random X chromosome inactivation ex vivo and in vivo. 19 Apr 2016

Developmental progression is linked to accumulation of epigenetic information mainly in the form of chemical modifications of the chromatin. One of the most striking examples of that is random X chromosome inactivation (XCI) in female mammalian embryos. This process is dependent on coating of one X chromosome by a long non-coding RNA, Xist. This in turn promotes rapid and dramatic remodelling of the chromatin. The functional relevance and exact spatio-temporal dynamics of this process remains elusive. Here I propose to address these questions by using an integrated approach. Firstly I will use an ex vivo embryo culture system to monitor the dynamics of XCI. I will further integrate that information with single cell and population based epigenomic to generate in vivo and in vitro datasets accounting to a roadmap for XCI. I aim at identifying the initial stages of epigenetic programming leading to transcriptional repression as well as genomic loci involved in nucleating these changes. I will finally address the functional relevance of X chromosome epigenetic programming by using gene knockout models and genome-wide single cell transcriptomics approach. Such work will have wide-raging implications beyond the field of XCI and can be extrapolated into other epigenetic regulatory mechanisms.

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

Anxiety in and about Africa 30 Apr 2016

We are applying for funding to support the travel of three speakers from the African continent. They will participate in a two-day interdisciplinary conference that examines the uses and meanings of the term ‘anxiety’ as it relates to Africa. The speakers will participate in a roundtable on the 'Vocabularies of Anxiety', which will explore how the languages with which we speak about Africa construct the continent as a site of anxiety. It will look at the importance of emotions like anxiousness in scholarly attempts to understand social, cultural, and political lives in Africa, and consider the dangers of employing a medical term as a heuristic device. Each speaker will bring a unique perspective on anxiety: personal anxieties about illness; psychiatric approaches to anxiety; and political anxieties about sexuality. By bringing together a range of research examining the various stimuli that may generate responses like anxiety we hope to invigorate an area of study that is still under-developed in the literature on Africa. Funding from the Trust will assist in bringing psychiatric and medical humanities perspectives to the fore, and ensure that African scholars are well represented.

Amount: £3,690
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulatory potential of repeat elements in the evolution of tissue-specific transcription 05 Jul 2016

The human genome, like all mammalian genomes, is in large part composed of decayed--but once active--repeat elements, many of which carry tissue-specific regulatory information. We hypothesise that repurposing of repeats has been critical for creating tissue-specific transcriptional regulation. Our research plan is an integrated experimental and computational strategy to systematically explore how these repeat elements have shaped the regulatory genome across the recent placental mammalian radiation.

Amount: £1,715,976
Funder: The Wellcome Trust
Recipient: University of Cambridge

Protein trans-activation of ribosomal frameshifting: a new paradigm in gene expression. 05 Jul 2016

Programmed ribosomal frameshifting (PRF) is a translational control mechanism widely used in the regulated expression of many viral, and several cellular proteins. The mRNA signals that induce PRF comprise a slippery sequence, where the ribosome changes into an overlapping frame, and an essential, stimulatory RNA structure which promotes frameshifting by modulating the ribosomal elongation cycle. Recently, we have uncovered two novel examples of viral PRF signals where frameshifting is trans-activated through the action of viral (cardiovirus 2A, arterivirus nsp1beta) and cellular proteins (poly(C) binding protein). The discovery of such protein-stimulated PRF opens up a completely new area in this field and offers novel opportunities for the study of protein-ribosome interactions. Our aim is to characterise the trans-acting factors and the mechanism by which they induce these novel PRF events. This will be achieved through a combination of functional assays, RNA-protein and protein-protein interaction studies and structural biology. This work will provide important new insights into ribosome structure and function, gene regulation, protein-protein and protein-nucleic acid interactions, virus replication strategies and virus-host interactions.

Amount: £774,356
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Mathematical Genomics and Medicine 30 Sep 2016

Imperial College London - Theoretical Systems Biology and Bioinformatics

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Developmental Mechanisms 30 Sep 2016

University of Cambridge 4 Year PhD Programme - Developmental Mechanisms

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Developmental Mechanisms 30 Sep 2016

University of Cambridge 4 Year PhD Programme - Developmental Mechanisms

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge - Infection, Immunity and Inflammation 30 Sep 2016

Cambridge - Infection, Immunity and Inflammation

Amount: £133,716
Funder: The Wellcome Trust
Recipient: University of Cambridge

An Interdisciplinary Investigation into Carolingian Medical Knowledge and Practice 10 May 2016

Focusing on the late eighth and ninth centuries, I am proposing an interdisciplinary project that aims to present a more comprehensive picture of Carolingian health and medicine than previous research has offered. I shall investigate early medieval medical knowledge and explore the question of its possible application through an in-depth analysis of textual sources supplemented by the skeletal record. Medical manuscripts shed light on the medical knowledge circulating among the literate elite, illustrating the perceptions of medicine within ecclesiastical communities, the movement of texts, and the adaptation and incorporation of classical learning in a Christian, medieval world. A review of the skeletal remains from cemeteries around the Frankish Empire during this period will provide insights into the health and lived experiences of people from all walks of life – including the vast majority of the population unrecorded by the texts. I shall compare the medical knowledge contained in the manuscripts with the palaeopathological and osteological record captured by the bones, asking: is there evidence that this knowledge was potentially applied? I hope to assess whether different types of communities and texts yield different answers. This interdisciplinary approach takes the study of Carolingian health and medicine in a new direction.

Amount: £94,637
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £227,598
Funder: The Wellcome Trust
Recipient: University of Cambridge

Exploring accessible nodes in the Unfolded Protein Response 05 Apr 2016

Protein folding homeostasis (proteostasis) in the endoplasmic reticulum (ER) intercedes in biological processes with consequences to diseases of aging. Cells cope with ER stress by addressing features common to most unfolded (and misfolded) proteins. Implementing the apparatus for this Unfolded Protein Response (UPR) entails tradeoffs that affect fitness in circumstance-dependent ways. Our research program is predicated on the notion that a detailed understanding of the UPR will identify failures of homeostasis that may be exploited therapeutically. We shall focus on four promising and underexplored nodes. The first two emerge from study of the signaling pathway by which cells downregulate global protein synthesis in response to ER stress, which hinges on phosphorylated translation initiation factor, eIF2a. We seek a detailed biochemical and structural understanding of eIF2alphaP dephosphorylation by PPP1R15-containing holophosphatases (whose inhibition promotes resistance to ER stress) and the action of eIF2B, a guanine nucleotide exchange factor [the target of eIF2(alphaP)]. Nodes 3 and 4 concern the machinery that regulates proteostasis by inactivating the ER chaperone BiP through enforced oligomerization or covalent modification. Delineating the UPR’s fundamentals is the foundation for the rapidly-advancing research into the experimental pathology of ER stress and fuels this important translational effort.

Amount: £4,424,281
Funder: The Wellcome Trust
Recipient: University of Cambridge

FlyBase: Communicating Drosophila Genetics on Paper and Online, 1970–2000 11 Jan 2016

The project will produce a history of FlyBase, an online database that orders and communicates genetic information about Drosophila. Established in the early 1990s, FlyBase was one of the earliest model organism databases and remains an essential routine tool for the Drosophila community. Taking on tasks previously accomplished by the paper-based Drosophila Information Service (DIS) newsletter and large, book-format mutant catalogues, FlyBase was representative of the transformation of biology into the highly collaborative, sequence-data-intensive, richly funded science it is today. Its history contributes to our understanding of that transformation. The goals of the project are (1) to provide a full picture of how disciplinary commitments and institutional politics shaped the community tools of Drosophila genetics, including DIS, the mutant catalogues and FlyBase; (2) to detail the history and development of the professional roles of ‘database genetics’; (3) to investigate how FlyBase changed the materials, practices, collaborations and organization of laboratory research in the 1990s; (4) to examine how FlyBase shaped Drosophila’s role as a model in biomedical research. I will thus recover the politics, infrastructures, professional expertise and practices of FlyBase and investigate what difference FlyBase has made to biology and biomedicine.

Amount: £152,518
Funder: The Wellcome Trust
Recipient: University of Cambridge