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University of Cambridge

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‘Pre-embryos’ Revisited: a historical sociology of translational biology 02 May 2017

This project will revisit the debates on human fertilisation and embryology that took place after the release of the Warnock report in 1984 and ended with the enactment of the Human fertilisation and Embryology Act in 1990. Firstly, it will ask how developmental biologist Dame Anne McLaren (1927-2007) used the scientific concept of the ‘pre-embryo’ as a rhetorical device in the debates to make the case for the continuation of research. McLaren’s role as the only research scientist on the Warnock Committee, but also in public debate and in the scientific community offers insight into the translational dimensions of human embryo research. Secondly, the research will explore the legacy of the term ‘pre-embryo’ by asking practicing developmental biologists conducting research that begs for an extended limit on in vitro research on human embryos, to reflect on the term in order to suggest which lessons about biological translation can be taken from the debates in the 1980s, and to assess the usefulness of new scientific terms and concepts when engaging lay-audiences in scientific debates.

Amount: £135,903
Funder: The Wellcome Trust
Recipient: University of Cambridge

Embryo architecture, potency and tissue interactions during mouse and human development 11 Jul 2017

Mammalian embryogenesis entails close partnership between embryonic and extra-embryonic tissues to regulate changes in embryo architecture and developmental potency. We aim for an integrated view of how these events progress hand in hand during key stages of mouse and human embryogenesis. The first architectural changes of the embryo are polarisation and compaction that trigger the separation of embryonic and extra-embryonic lineages. Yet their own trigger remains unknown. We will dissect potential triggering pathways and through genetic manipulations determine their importance for cell fate. Embryo remodelling at implantation is intimately associated with pluripotent-state transitions. We will harness our novel techniques for embryo culture throughout implantation to uncover mechanisms behind these events in relation to signalling partnerships between embryonic and extra-embryonic tissues. By arranging partnership between embryonic and extra-embryonic stem cells in 3D-culture we have recapitulated embryo-like morphogenesis and spatio-temporal gene-expression. We will characterise tissue interactions in such stem cell-derived embryos to understand principles of self-organisation. Our work established an unprecedented opportunity to study human early post-implantation embryogenesis in-vitro. We will build the first morphological and transcriptional atlas of human development beyond implantation. This will bring understanding of normal development and shed light upon why many pregnancies fail at early stages.

Amount: £2,135,983
Funder: The Wellcome Trust
Recipient: University of Cambridge

Self-propagating protein conformations as targets of intracellular immunity 22 Feb 2017

Recent discoveries in neurodegeneration support the cell-to-cell transmission and replication of certain ‘prion-like’ proteins in a manner highly reminiscent of viral infection. This suggests that antiviral mechanisms could potentially be used to treat neurodegenerative diseases. The novel antibody receptor TRIM21 engages immune complexes in the cytoplasm and elicits their proteasome-dependent destruction. This activity prevents infection by viruses that enter the cell with antibodies attached to them. Preliminary data show that seeds of tau, a cytoplasmic prion-like protein that aggregates in Alzheimer’s disease, can similarly be neutralized in this way. This study will combine high-content cellular seeding assays, degradation assays and two mouse models of tau pathology to investigate the mechanism of antibody protection during immunotherapy. Using antibody engineering and knockout mice lines, I will quantify the contribution of TRIM21 and classical Fc receptors to immunotherapeutic protection against neurodegeneration. I will determine how cellular machinery elicits the inactivation of prion-like proteins. This combined approach will support an understanding of intracellular inactivation of prion-like proteins and relate it to disease progression. Current understanding has not translated into disease-modifying therapeutic interventions for neurodegeneration. These studies may inform new strategies aimed at limiting spread of pathogenic protein assemblies using antibodies.

Amount: £964,847
Funder: The Wellcome Trust
Recipient: University of Cambridge

Role of neuronal nitric oxide in the vasodilatory response to mental stress 27 Apr 2017

Nitric oxide (NO) is a potent regulator of vascular tone. Until relatively recently, it was assumed that the isoform of NO synthase responsible for tonic NO release was endothelial nitric oxide synthase (eNOS). However, we now know that in humans, neuronal NOS (nNOS) is the primary NOS isoform responsible for regulating vascular tone in vivo. Neuronal NOS is also activated by mental stress and contributes directly to resistance vessel vasodilatation. However, our preliminary data indicate that this response is biphasic, suggesting a second mechanism underlying the vasodilatory response to stress. We hypothesise that this additional mechanism may be mediated through agonism of beta2 adrenoceptors. This hypothesis will be tested in healthy volunteers exposed to mental stress (Stroop test), using the gold-standard technique of venous occlusion plethysmography to measure forearm blood flow, coupled with intra-arterial infusions of selective inhibitors of nNOS and beta2 adrenoceptors. The key goals of this research are (i) to better define the regulation of vascular tone in healthy humans with a view to understanding potential mechanisms underlying vascular dysfunction in disease states; and (ii) gain a broader understanding of early experimental medicine approaches in the clinical setting.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Identification of the active eIF4E in trypanosomes 27 Apr 2017

A detailed understanding of the initiation of translation in kinetoplastid pathogens is still elusive. There is an innate complexity due to the number of isoforms of eIF4E and eIF4G, two of the three components of eIF4F. Second, there has been no simple way to rapidly ablate expression of a protein to render an immediate phenotype. RNAi is available but it takes 3 to 4 cell cycles to dilute the eIF4E sufficiently to detect a phenotype and then is difficult to distinguish primary and secondary phenomena. We have recently developed a system for the inducible ablation of a specific protein in less than 60 minutes. This summer studentship will exploit this method to ablate separately the two isoforms of eIF4E that probably are responsible for mRNA cap binding during translation initiation. An analysis of the qualitative and quantitative effect on protein synthesis after ablation will inform on whether the two eIF4E isoforms have different, overlapping or identical functions. The work builds on expertise in the lab and utilizes a new technique to answer a long standing question.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Gurdon Institute Centre Renewal 30 Oct 2016

The Gurdon Institute focuses on several related topics at the interface between developmental biology and cancer: Cell division, proliferation and genome maintenance; Function and regulation of the genome and epigenome; Mechanisms of cell fate determination, multipotency and plasticity; The cell biology of organ development and function. We investigate these areas in both normal development and cancer using several model systems, with an increasing emphasis on organoids. Our five-year vision is to expand our research in two strategic directions: Human development and disease We will study the development and homeostasis of tissues and organs using human organoid systems. We will also develop new models of human diseases, including cancer, using organoids and patient-derived stem cells. Quantitative analysis of cellular dynamics We will analyse developmental and disease processes quantitatively at the molecular, cellular and tissue scales, using next generation sequencing and imaging approaches. We will also increase our collaborations with physical scientists expert in analysing the complex datasets generated by these approaches. We plan to continue to translate our research into new therapies. This will be enhanced by the establishment of the Milner Institute, which will provide a platform for collaborations with pharmaceutical companies on disease models emerging from our research.

Amount: £13,247,091
Funder: The Wellcome Trust
Recipient: University of Cambridge

Diagnostically cross-cutting intermediate phenotypes of impulsivity and compulsivity. 19 Nov 2015

The proposed research will deconstruct impulsivity and compulsivity using cutting-edge neurocognitive tests, structural and functional neuroimaging, pharmacological challenge of the brain dopamine/adenosine systems, and quantification of peripheral dopamine status. In this way I aim to link cognitive and brain systems phenotypes of impulsivity/compulsivity to more mechanistically specific markers of abnormal neurotransmission and to demonstrate how these intermediate phenotypes are expressed dim ensionally in the population, and cut across two major diagnostic categories of psychiatric disorder. The key goals will be to address three core hypotheses: 1. That underlying intermediate phenotypes of impulsivity/compulsivity (measured using neurocognitive tests and psychopathology questionnaires) manifest as extremes of the normal population distribution (in the absence of overt psychiatric disorders) and, similarly, in classical psychiatric disorders of impulsivity and compulsivity (atte ntion-deficit hyperactivity disorder and obsessive-compulsive disorder). 2. That these intermediate phenotypes of impulsivity/compulsivity emerge as a consequence of altered fronto-striatal activity, and are under the modulatory influence of brain dopaminergic and adenosine neurochemical systems. 3. That these intermediate phenotypes of impulsivity/compulsivity, and their tractability to dopaminergic and adenosine drug manipulations, are correlated with peripheral blood-based biomarkers o f dopamine function.

Amount: £989,383
Funder: The Wellcome Trust
Recipient: University of Cambridge

The biology of acute myeloid leukaemia 30 Sep 2016

Mutations in epigenetic regulators play a pivotal role in leukaemia initiation. We propose to study the most commonly mutated epigenetic regulator in AML: the de novo DNA methyltransferase DNMT3a (25%). It is unclear how DNMT3a mutations subvert HSC, surprisingly in bulk studies differences in methylation do not correlate with differences in gene expression, but somehow DNMT3a mutated HSC have an advantage in xenografts and survive apparently successful chemotherapy in 80% of patients. Even if a persistent clone does not predict relapse rate these patients tend to have a poorer prognosis. DNMT3a mutations are also the most prevalent in individuals with "clonal haematopoiesis". To study DNMT3a mutated preleukaemia we will use a mouse model where the most common DNMT3a mutation (R882H) and an RFP are under the control of the Mx1-cre promoter. By titrating the dose of pIpC we will generate a chimeric mouse where only ~ 20% of cells express the mutant allele. We will study clonal dynamics after challenging HSC homeostasis (through lineage tracing of the RFP) and document alterations in gene expression at the single cell level at baseline and after perturbing HSC using state-of-the-art technology (Polaris system). We will then corroborate our findings in human DNMT3aR882 preleukaemia.

Amount: £252,167
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £244,848
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

Engaging the public in health services research 15 Sep 2016

Engaging the public in health services research Engaging the public in health services research

Amount: £100,000
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

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

Establishing an in vitro model for embryonic patterning using a novel micropatterning system 11 Nov 2015

An in vitro micropatterning system (MPS) was developed, using human ESCs, which apparently mimics patterning within the embryo. This 'embryo in a dish' develops a presumptive primitive streak, introducing the possibility of studying gastrulation dynamically in vitro. This MPS gastrulation model resembles 3D organoids emerging for a number of systems and enables signalling manipulation in time and 3D space. While this system was established in human, it cannot be validated by comparisons with in vivo human development. The mouse model represents an essential bridge between pluripotent cell cultures and the embryo. I will establish the MPS in mouse and compare the expression of lineage markers in the MPS directly to mouse embryos to ask whether this system recapitulates in utero development. I will use the MPS to compare mouse and human development and analyse the basis of patterning defects in mouse mutants. I will use transcription factor and signalling pathway fluorescent reporters to map the spatial and temporal requirements of BMP, Activin/Nodal and Wnt pathways for patterning at a quantitative single cell resolution in real-time. Using this data, in collaboration with the Siggia lab, mathematical models will be generated and tested to predict the phenotypic outcome of signalling combinations.

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

Ischia Summer School on the History of the Life Sciences 31 Aug 2016

The Ischia Summer School on the History of the Life Sciences provides advanced training in history of biology and medicine in a historically rich and naturally beautiful setting for 26 PhD students and postdoctoral fellows, with strong UK representation. Lectures and seminars at the Ischia branch of the Naples Zoological Station by nine distinguished international faculty, with student presentations and discussions, encourage exchange of ideas across academic cultures. The 15th school, scheduled for 24 June – 1 July 2017, is on ‘Cycles of Life’, which we understand to range from ancient cycles of generation and corruption, the seasons and the weather cycle to modern reproductive, metabolic and ‘biogeochemical’ cycles, as well as contraceptive interventions in menstrual cycles and strategies to disrupt pest and pathogen life cycles. We will trace connections and identify patterns of continuity and change, explore shared properties of cycles and the differences and relations between disciplines and research programmes. The Naples Station will grant use of facilities, NSF will cover the costs of American participation and students will each pay €300. We are very grateful to Dan O'Connor for inviting an application and would be thrilled if the Trust could provide the balance of the funds.

Amount: £19,960
Funder: The Wellcome Trust
Recipient: University of Cambridge

Adapting the human intestinal epithelial organoid culture model for the use in paediatric and GI disease 01 Apr 2016

Inflammatory Bowel Diseases (IBD) are still not entirely understood, particularly the mechanisms that lead to their development in patients. Despite the research community's efforts little or no evidence of a genetic predisposition can be identified. Meanwhile the incidence of IBDs has been increasing, especially in western and westernised countries. Epigentics poses an interesting research target for finding the link between environmental changes and the incidence of IBDS. It has already been shown to effect gene expression in other systems and could prove key in linking our environment to the observation of the IBD phenotype. DNA methylation is one of the most widely researched epigenetic mechanisms to date, and involves the attachment of a methyl group to the 5' position on the pyrimidine ring of the nitrogenous base, Cytosine. Through increased methylation, the chromatin state is repressed and transcription is inhibited. Patients with IBDs exhibit a distinct isolated distribution of inflammation, suggesting that molecular changes have occured within the specfic gut segment. We intend to use isolated DNA and RNA from gut biopses to test the hypothesis that aberrant DNA methylation in the intestinal epithelium is either the cause and/or contributes to the observed relapsing, inflammatory phenotype in patients with IBD.

Amount: £1,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

Hydroxylation as a mechanism for regulating the deubiquitinating enzyme OTUB1 01 Apr 2016

The hypoxic response is an evolutionary conserved mechanism that allows cells to survive low oxygen levels, by promoting activation of genes that regulate metabolism, angiogenesis, redox homeostasis and immunity. Central to this pathway are the hypoxia inducible transcription factors (HIFs) that are regulated by hydroxylase enzymes that sense intracellular oxygen levels and modify HIF activity. The role of these hydroxylase enzymes outside of the HIF pathway was unclear, but we have recently shown that the asparagine hydroxylase, factor inhibiting HIF (FIH), modifies the deubiquitinating enzyme, OTUB1, altering metabolic responses within the cell. However, how asparagine hydroxylation of OTUB1 regulates its enzymatic activity is not known. Therefore, in this project we will use an in vitro assay that we have established to determine how asparagine hydroxylation of OTUB1 regulates its deubiquitination activity and whether hydoxylation prevents binding to other ubiquitin enzymes. This vacation project offers an excellent introduction to protein biochemistry in an area of important scientific interest, and complements ongoing research within Dr Nathan’s laboratory.

Amount: £1,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

The characterisation of T7 polymerase amplifier devices and arsenic repressor/promoter combinations in B. subtilis for use in the development of an Arsenic Biosensor. 01 Apr 2016

Harnessing the natural arsenic sensing ability of the bacteria Bacillus subtilis, it has been possible to engineer strains that synthesise a visible pink chromoprotein at different threshold concentrations of arsenic (10, 50 and 200 ppb), corresponding to WHO and government-recommended guidelines for arsenic levels. The constructed strains now require extensive characterisation of individual components of the system. This project aims to characterise the signal-amplifying devices for T7 polymerase and split T7 polymerase, along with several arsenic repressor-promoter combinations. This will be achieved by transferring the desired devices into a pre-designed dual reporter strain of B. subtilis by PCR/molecular cloning/chromosomal integration. The production of fluorescent reporters in plate reader assays for different arsenic concentrations, will allow characterisation of the device output. The performance of these parts and devices across a range of arsenic concentrations and incubation regimes (temperatures, fluctuating temperatures etc.) will also be addressed. The development of an Arsenic Biosensor would effectively address the global issue of arsenic contamination of ground water in a low cost, accessible and sensitive manor.

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

The role of the mitotic spindle assembly checkpoint (SAC) protein BUB3 in tumourigenesis. 13 Apr 2015

The spindle assembly checkpoint (SAC) ensures the correct partition of chromosomes during mitosis. Depleting SAC proteins together with apoptosis inhibition leads to tumourigenesis. This project builds on a tumourigenesis model in Drosophila to address the role of SAC in hyperproliferation, metabolic regulation and tumour evolution. Initially I will study candidate genes uncovered by microarray analysis of a tumour generated by knocking down the SAC gene Bub3. As the cells' metabolic response ad apts to proliferation requirements it is clear that there must be a cross talk between cell cycle and metabolic control. To address this hypothesis, an enhancer/suppressor screen looking for metabolic proteins with links to cell cycle will be performed. The tumorigenic model derived from cell cycle defects affecting genomic integrity, will also be used to study tumour evolution. The use of a tumourigenesis fly model will exclude some difficulties of these studies in humans as tumours can be samp led at multiple stages. In addition, the tumour growth will not be limited by the life span of the hosts as the immortalized tumour can grow indefinitely through serial transplantations in inbred flies. Altogether the results will identify novel genomic loci and alterations responsible for tumour growth and cellular survival.

Amount: £446,052
Funder: The Wellcome Trust
Recipient: University of Cambridge

WACCBIP-Wellcome Trust DELTAS Programme 05 May 2015

The proposed DELTAS Programme seeks to strengthen and extend the scope of the mission of the West African Centre for Cell Biology of Infectious Pathogens (WACCBIP: www.waccbip.org), which was established at the University of Ghana (UG) in 2013. We believe that the vision of the DELTAS initiative aligns perfectly with our own aspirations at WACCBIP, where our mission is to improve diagnosis, prevention and control of tropical diseases by providing advanced level training and research on the cell and molecular biology of infectious pathogens. WACCBIP faculty are drawn from the Department of Biochemistry, Cell and Molecular Biology (BCMB), and the Noguchi Memorial Institute for Medical Research (NMIMR) at UG as well as seven partnerinstitutions within Africa. International faculty include several leading scientists from UK institutions, and members of the American Society for Cell Biology. WACCBIP was selected by the World Bank as one of the African Centres of Excellence for Higher Education, and received funding to build capacity for training of PhD and Masters students in Biochemistry and Molecular Cell Biology. This application seeks support from the DELTAS scheme for increased impact and long-term sustainability in the following ways: 1. Develop the first graduate and professional Human Genetics programme in Ghana, which will complement our existing pathogen biology research training. This programme will provide a structured research training platform to synergize with existing genetics training programmes led by the H3Africa network. 2. Develop a post-doctoral programme to help keep newly qualified PhDs in Africa and attract African scientists who have completed their PhDs abroad to return home. These postdoctoral fellows will conduct supervised research at WACCBIP and its regional partner institutions. 3. Strengthen our co-supervisor system through a Student Visitor programme, sothat PhD students and postdocs will be funded for six-month visits to the laboratories of cosupervisors in the UK or USA to hone their research skills. 4. Strengthen the mentoring system so each postdoctoral and PhD trainee will have a local mentor and access to advice from a UK or US scientist. 5. Develop a short course in research ethics that will be run annually to train young African scientists on responsible conduct. The goal of the proposed programme is to provide advanced training of health professionals and increase research and innovation to guide development of new approaches to disease diagnosis, prevention, and control. Effective training programs must be anchored by a strong, well-structured, and focused research portfolio. Therefore, this application seeks to build on our strength in pathogen biology research by incorporating a genetics curriculum and research platform, which is critical for a complete understanding of disease mechanisms for both communicable and noncommunicable diseases. Thus, the proposed research training will incorporate genetics into the study of host-pathogen interactions, as well as in investigating the molecularmechanisms that predispose individuals to the development of non-communicable diseases. This application builds a coalition of local, regional and international partners who have advanced resources and expertise in human genetics and pathogen biology research to support the proposed training programmes.

Amount: £132,017
Funder: The Wellcome Trust
Recipient: University of Cambridge