- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
To be submitted later
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.
Steroid Receptor Coactivator-1 (SRC-1) is coactivator for various transcription factors (TFs) and nuclear hormone receptors (NRs). In rodents, SRC-1 plays a role in the regulation of energy balance and glucose homeostasis by activating ligand-bound nrs and TFs. We have recently identified 15 novel mutations in this molecule using whole exome sequencing and targeted resequencing of 2548 patients with severe early onset obesity (Genetics of Obesity Study: GOOS). In addition to obesity, these patients have other symptoms, including disproportionate insulin resistance and chronic diarrhoea. We hypothesise that human SRC-1 mutations directly impair the interaction with pSTAT3 to cause severe obesity, and impair NR-mediated gene expression, to cause insulin resistance and intestinal dysfunction. I propose to undertake the detailed functional and clinical characterisation of SRC-1 mutations. I will use HEK-293 cells to characterise the functional consequences of SRC-1 mutations, particularly focusing on their interaction with STAT3 and NRs. Patients will be invited to take part in clinical studies in which we will assess energy and glucose homeostasis, body composition and the circulation of bile salts. This work will improve our understanding of obesity, and shed light on mechanisms underlying patients’ symptoms to inform further work including interventional studies.
DNA viruses, such as Herpes Simplex Virus 1 (HSV-1), exploit specific host DNA repair mechanisms to assist their replication. More recently, the DNA repair machinery that senses damaged self-DNA was shown to function in the innate immune sensing of viral DNA during infection. We aim to understand how a specific DNA repair pathway, non-homologous end joining, affects HSV-1 infection and how this virus exploits or evades these host responses. This work will further our knowledge of cell-intrisic immunity and DNA repair as well as leading to the rational design of improved vaccines and oncolytic viruses. Our preliminary data indicate that two NHEJ proteins, DNA-PKcs and PAXX act to restrict HSV-1 in different ways, via activation of innate immune responses or by directly affecting virus replication. This study will provide the mechanistic basis of these observations and compare these data with the other components of the NHEJ machinery and how they regulate HSV-1 infection. This work will therefore explore two hypotheses: NHEJ proteins regulate innate immune sensing of HSV-1 DNA NHEJ proteins restrict HSV-1 replication in the nucleus
A new approach to OCD: assessing the impact of environmental stimuli on functional and dysfunctional checking behaviour. 14 Dec 2015
Obsessive-compulsive disorder (OCD) is a common and highly debilitating mental health disorder, which could be potentially treated through the disruption of maladaptive memories that contribute to the persistence of the disorder. Using an instrumental rodent model of OCD, the Observing Response Task (ORT), in which animals are trained to make unpredictably reinforced instrumental responses, but can check which response will be reinforced by pressing an ‘observing’ lever, we can dissociate functional and dysfunctional checking responses. Using this task, we have begun to investigate the influence of environmental cues on the development of maladaptive checking. We hypothesise that threatening, anxiogenic pavlovian cues in the environment promote the development of functional checking to reduce uncertainty, but that the conversion of these behaviours into dysfunctional, maladaptive responses is promoted by appetitive pavlovian cues. The proposed research aims to extend our preliminary findings, examining whether the relationship between sensitivity to aversive and appetitive pavlovian cues and the development of functional and dysfunctional checking is correlative or causal, and to determine the influence of appetitive and aversive cues on the development of compulsive checking. This would provide a springboard for future studies attempting to disrupt the reconsolidation of these maladaptive memories.
Investigating the link between genome reduction and pathogenicity using an emerging zoonotic pathogen. 21 Oct 2015
Bacterial pathogens very often have smaller genomes and fewer genes than their nearest non-pathogenic relatives. This pattern applies in phyla as diverse as the Firmicutes, Tenericutes and Proteobacteria. However, despite much speculation, it remains unclear why this pattern holds. I will address this question using Streptococcus suis, a bacterium that is common in non-pathogenic forms, but which also causes serious diseases in pigs and humans. My preliminary data show that S. suis has made seve ral recent and independent transitions to pathogenicity, each associated with genome reduction, and that the gene loss is non-random, suggesting that the process might be predictable. I propose to sample whole genomes of global S. suis populations. Then, I will carry out the first large-scale tests of the various hypotheses linking genome reduction and pathogenicity. This will require functional data, and new statistical approaches. Next, I will use methods from Bayesian phylogeography to place the genome reduction events in their epidemiological context, identifying factors that lead predictably to increased virulence. Finally, I will use genome reduction as a tool to uncover new virulence genes. Together, the proposed research will further our understanding of an important emerging pathogen, and of pathogenicity much more broadly.
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.
Makerere University UVRI Centre of Excellence for Infection & Immunity Research and Training (MUII-plus) 05 May 2015
Infectious diseases remain the commonest cause of death in Africa, with HIV, malaria, tuberculosis and respiratory infections major contributors (Figure 1).1 Neglected infectious diseases cause widespread morbidity and economic loss.2 Yet effective vaccines are lacking for HIV, malaria, tuberculosis and helminths, and improved diagnostics and interventions are required. Concurrently, escalating non-communicable disease (NCD) rates3 present opportunities to explore infection-NCD relationships in ways no longer possible in resource-rich settings4 and genetic studies promise new insights into immunobiology because genetic variability in Africa is so high.5, 6 These African challenges and opportunities call for Infection & Immunity (I&I) research, in which key disciplines are immunology, molecular biology and bioinformatics. High infectious disease endemicity means that African scientists have unrivalled opportunities to conduct translational I&I research of global importance, embedded within strong epidemiological study designs (Figure 2). However, strong African capacity is necessary for sustainable, regionally-based research on African health priorities, and development in basic sciences has lagged behind clinical and epidemiological expertise.7 In Uganda, this gap hasbeen recognised: the National Development Plan8 and Vision 20409 prioritise science investment; basic science is a research priority at Makerere University;10 an African Development Bank (ADB) loan is developing laboratory infrastructure at Ugandan institutions (question(q)1j-k). The Makerere University UVRI Centre of Excellence for Infection and Immunity research and training (MUII-plusi) strategy is to drive I&I science in Uganda by bringing together scientists from the foremost health research institute (the Uganda Virus Research Institute, UVRI), and foremost university (Makerere), with their world-class, external collaborators, to support excellence in I&I research and training. Building on experience since 2008, and aligning with the Trust's DELTAS strategy [indicated in italics] MUII-plus will 1. Promote Africa-relevant I&I scientific excellence [Scientific Quality]. Transitioning from a training programme, the MUII-plus Centre of Excellence will comprise senior Ugandan I&Iscientists and young, emerging leaders, their research groups, trainees, and international collaborators: a mutually-supportive platform for world-class Africa-relevant science and training. 2. Provide career training for African I&I research leaders [Research Training] through a. Career-pathway fellowships: Uganda-based, with international collaboration and cosupervision b. Focus on bioinformatics: ring-fenced bioinformatic fellowships and project grants; shortcourses integrated with partner-network opportunities c. Focus on emerging & re-emerging infectious diseases: ring-fenced PhD opportunities at College of Veterinary Medicine, Animal Resources and Biosecurity (CoVAB) d. Improved efficiency and quality in I&I Masters training: Coordination of courses across Makerere colleges; expert input from Uganda partners, and video-conferencing from Cambridge e. Professional development and citizenship: mentored leadership experience; curriculum of workshops f. Planning for sustainability and succession 3. Utilise and enhance the UVRI-Makerere I&I research environment [Management/Environment]: a. Drive research in new laboratories developed during phase 1 (MUII-1i), in new, CoVAB, biosecurity laboratories, in the MRC-funded Uganda Medical Informatics Centre b. Strengthen research support at lead institution, UVRI 4. Engage in outreach [Citizenship]: developing communication skills; raising public awareness, networking scientists and trainees, sharing resources and research findings, interacting with policy makers, promoting implementation
Apical-basal polarity is essential for all aspects of epithelial cell function and loss of this polarity is a hallmark of cancer. We have recently found that the endodermal epithelium of the Drosophila adult midgut polarises by a different mechanism from other Drosophila epithelia and may provide a good model for endodermal epithelia in mammals. This proposal aims to understand how polarity is generated in both epithelial types. Firstly, we will examine how the canonical polarity complexes polarise the secretory epithelium of the Drosophila follicle cells. We will investigate how Cdc42 is activated to define the apical domain; we will use optogenetics and super-resolution microscopy to investigate the dynamics and composition of polarity complexes; and we will analyse how cortical polarity organises the microtubule cytoskeleton through the lateral polarity factor, Par-1. Secondly, we will perform clonal screens to identify essential epithelial polarity factors in the Drosophila midgut and characterise their functions. To test whether these factors play conserved roles in mammals, we will knock out their orthologues in mouse intestinal organoids. This research will reveal the fundamental mechanisms that polarise different epithelial types, which is an essential prerequisite for understanding epithelial function and how it is perturbed in diseases like cancer.
Integral membrane protein cargo are constantly moved in coated tubular/vesicluar carriers between the cell's organelles and its limiting membrane in order to maintain membrane identity and function. That these transport processes are of fundamental importance is reflected by the fact that ~30% of mammalian proteins are either components of the vesicle/tubule transport machinery or are its cargo. Coated vesicular/tubular carrier formation including cargo selection requires the interplay of a network of peripheral membrane proteins and membrane components including phospholipids, small GTPases, docking proteins and the cargo itself. The coat must also prepare and facilitate the carrier for fusion with its target. AP2, AP3, COPI and retromer/VARP based coats along with their accessory/regulatory factors are vital for producing a fully functional endosomal system. We will use a combination of X-ray crystallography, NMR and the fast developing techniques of single particle cryoEM and cryo electron tomography allied with biochemical/biophysical studies to formulate theories concerning the architecture, assembly routes and control/regulation of the formation of these four key tubular/vesicular transport carriers. Specific function abolishing mutations designed on the basis of these studies will allow us to test and further explore our theories in cells using a wide range of in vivo techniques.
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.
Our overarching aim is to gain insights into the biology of enteropathogenic caliciviruses, focusing on the fundamental aspects that have remained elusive to date: viral entry into target cells, the interplay with the host innate response and the recruitment of host-cell co-factors that support replication. Having significantly improved the culture systems for human noroviruses and developed reverse genetics, we now have the first opportunity to study human norovirus replication in a physiologically relevant system. We will focus on three areas: 1. C-type lectin receptors (CLRs): We have found that CLRs may work in concert with blood group antigens to allow norovirus infection. We will further dissect the role of CLRs in the norovirus life cycle. 2. Innate responses to infection: We have found that type I/III interferons restrict norovirus replication but that infection induces the COX-2/PGE pathway to promote replication. We will dissect the response to infection in the organoid system and characterise a novel virus-encoded regulator of the NF-kB system. 3. Trans-acting factors: We will examine their role of a number of host factors (VapA/B, Squle and PI4Kalpha) in norovirus replication and expand this study to an undertake an unbiased analysis of the human norovirus replication complex.
The goal of this research proposal is to build a theoretical and experimental framework to understand the contextual determinants of "surprise" (expectation violations/prediction errors) in health, development, and disorder. I have the following three aims: 1) To exploit high-field neuroimaging and pharmacological manipulations in healthy adults to reveal the precise neural mechanisms that alter surprise processing in response to volatility, and validate different pupil metrics as a window into central neuromodulatory function. 2) To conduct model-based neuroimaging in infants, for the first time, to predict risk for the dimensional symptoms of autism, and reveal the computational neurodevelopment of probabilistic and volatility learning in infants. 3) To develop a unified computational framework of surprise-driven learning that has the specificity to reveal separable mechanisms of psychopathology in different neuropsychiatric conditions and the potential to be used as a clinical tool. To achieve these objectives I will utilise the same cognitive tasks, pupillometric measurements and computational models of learning across three research themes. This ensures that while the individual projects are strongly hypothesis-driven the findings can be directly translated across developmental, adult, and disordered states. Key words: autism, neurodevelopment, predictive coding, surprise, computational models, 7T fMRI, pharmacology, noradrenaline, psychosis.
The nuclear envelope (NE) lies at the interface between the nucleus and the cytoskeleton. It forms a complex structure controlling cell compartmentalization and regulates many processes including nucleo-cytoplasmic transport of proteins and RNA, chromatin organization, DNA replication and DNA repair. Hence, defects in NE integrity and nuclear architecture cause drastic changes in cell homeostasis and are associated with a broad range of diseases including cancer, premature ageing syndromes, neurodegenerative diseases or muscular dystrophies, but also with physiological ageing. One of the main challenges is to understand how NE defects lead to so many types of diseases. Previous theories include changes in gene expression and mechanical weakness. My previous work has shown that subcellular processes including microtubule or chromatin organization can modulate NE function, and has identified the acetyltransferase NAT10 as a key regulatory node for control of nuclear architecture. My goal is to now investigate how NAT10 and other factors regulate the NE. I will thereby gain new understanding of how of nuclear architecture is orchestrated and how this is disrupted in age-related diseases including HGPS. This research will not only contribute to our fundamental understanding of nuclear architecture but will also potentially identify new therapeutic strategies for NE-associated syndromes.
Anti-tumour 'type-1' immunity is driven by NK cells and cytotoxic CD8 T cells, while T helper type-2 (Th2) cells are associated with a pro-tumourigenic phenotype. Group 2 innate lymphoid cells (ILC2) are the innate counterpart of Th2 cells, and are locally activated by epithelial derived alarmins. While recognised as central orchestrators of 'type-2' inflammation in allergies, there is no evidence for their importance in shaping a pro-tumourigenic environment, despite the known roles of alarmins in tumourigenesis. My preliminary data reports the presence and profound enrichment of ILC2 in pancreatic intraepithelial neoplasias (PanIN) as they progress to pancreatic ductal adenocarinoma in P48-Cre LSL-KrasG12D (KC) mice. I will resolve the role of ILC2 in pancreatic carcinogenesis using an orthotopic implantation model in conjunction with next-generation ILC2-targeted reagents and intravital imaging. Secondly, I present preliminary data that suggests a negative-feedback mechanism by which lung ILC2 dampen the anti-tumour immune function of NK cells. I will use exclusive ILC2-targeted reagents to resolve this mechanism, and its effect on lung metastasis formation. As tissue resident immune-modulators, ILC2 may provide a critical new target in cancer therapy.
Exploring Disorganised Attachment: Unravelling Developmental Pathways and Outcomes using Data Mining 30 Jun 2017
Disorganised attachment is an important assessment of infant mental health, introduced by Main and Solomon (1990). Disorganisation is thought to result from an infant having in some way experienced trauma within the context of the relationship with their caregiver (e.g. observing severe domestic violence). Infants classified as disorganised have an elevated risk of psychological problems, most notably conduct disorders (Fearon et al. 2012). The possibility of a finer-grained measure emerged out of archival research, under Duschinsky's New Investigator Award, on the original Berkeley dataset from which disorganised attachment was first identified. As a result of the significant stakes for research and clinical practice, we have been offered unprecedented access to a remarkable longitudinal dataset to explore a) how the finer-grained measure fares against the standard construct in predicting a range of negative outcomes, and b) whether particular forms of disorganisation have specific antecedents. Given that the goal is exploratory and the array of relevant measures is extensive, data mining will be used rather than hypothesis-testing. The research offers the prospect of a significant transformation of research in this area. Three focus groups with clinicians will be conducted to facilitate clinical input and translation.
There is a growing recognition that research should be carried out in an open fashion, making data available early and in a reusable form to maximise worldwide research output. However, fulfilling this promise requires front-line researchers to comply with current data management standards as required by the data policies of funders and journals. These are additional burdens to research that will give them little immediate return. Thus we propose to create a cloud-based, open-source, extensible data collection and presentation platform that will provide scientists with: (1) immediate reward for their annotation efforts through sharable data visualisation, integration outputs and exploration tools; (2) standardised web services to facilitate script-based data manipulation and analysis; (3) an easy-to-use pipeline for preparing their data for publication; (4) incentives to improve data quality, accessibility, and machine-actionability at the appropriate level of granularity; and (5) allow institutions and other parties to host the platform to ensure its availability and reliability. We will do this by building on the success and complementarity of the ISA tools suite (Oxford) and the InterMine platform (Cambridge) to make it quicker and easier to generate rich integrated dynamic web sites at single paper/lab scale up to consortium scale.
Developing an in vivo MT nucleation assay to investigate g-tubulin independent centrosomal MT nucleation 27 Apr 2017
Centrosomes are major microtubule organising centres (MTOCs) in animal cells. During mitosis they recruit large numbers of gamma-tubulin ring complexes (g-TuRCs), which nucleate and anchor the microtubules required for spindle formation. Recent work in the Conduit lab has surprisingly shown that centrosomes lacking g-TuRCs can still organise microtubules. Nevertheless, it remains unclear if these microtubules are generated at centrosomes, or generated in the cytoplasm and then anchored at centrosomes. I aim to establish an in vivo microtubule nucleation assay to test these alternative possibilities. Drosophila larval brains, which are highly mitotically active, will be dissected from either wild-type flies or from mutant flies where the centrosomes lack g-TuRCs. They will be cooled on ice for 40 minutes in order to depolymerise all microtubules and then transferred to 25 degrees and chemically fixed at different timepoints. The brains will be stained for microtubules, centrosomes and mitotic DNA using antibodies already available in the Conduit lab and images will be taken on a confocal microscope. The location and intensity of new microtubule growth will be assessed. If the g-TuRC negative centrosomes do nucleate microtubules, the assay will be used to test candidate proteins for their role in centrosomal non-g-TuRC mediated microtubule nucleation.
Determining the Significance of Pathway Bias at the Calcitonin Gene-Related Peptide Receptor Family in Human Endothelial Cells 27 Apr 2017
Family B G protein coupled receptors (GPCRs), notably the calcitonin like receptor (CLR), have been implicated in cardioprotective functions. The functional GPCR is a heterodimer of CLR and one of three possible receptor activity-modifying proteins (RAMPs). There are 3 main agonists for this GPCR: calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and adrenomedullin 2 (AM2). CLR is pleotropic, activating intracellular pathways through coupling to G proteins or beta-arrestins. Indeed, we recently showed, using both a heterologous yeast expression system and mammalian (HEK-293) cell lines, that the signalling bias of the CLR is dependent upon both the agonist and the RAMP. However, the cell environment of the receptor massively affects signalling bias. Therefore, to validate these results, investigation of the pharmacology of the CLR in endogenous cell lines is essential. The aim of this research is therefore to use two different human cell lines (HUVECs and HUAECs) to pharmacologically investigate CLR/RAMP2 (the adrenomedullin receptor) and CLR/RAMP1 (the CGRP receptor) when endogenously expressed. It is hoped that this will provide greater insight into the function of CLR signalling in the vascular endothelium. This information may then be used to help characterise the pathophysiology of common cardiovascular diseases such as hypertension and myocardial infarction.
We have shown that local control of RNA and protein metabolism by ribonucleoprotein granules plays a vital role in synaptic function. Recently, we discovered that the RNA binding protein, FUS, physiologically transitions between dispersed, liquid droplet and hydrogel states. These transitions, driven by its LC domain, underpin reversible assembly of FUS granules and regulate protein synthesis in nerve terminals. Crucially, pathogenic FUS mutations induce irreversible assembly and RNP granule dysfunction. Our results raise questions about how FUS assembly is regulated, how it affects synaptic activity, and causes disease. To address these questions, we will use bioinformatics, proteomics, and iCLIP to identify key modulators (posttranslational modifications, interacting proteins) (Aim 1). We will use soft matter physics to investigate their impact on FUS assembly (Aim 2). We will apply advanced single molecule imaging tools to assess how modulators affect granule function (Aim 3). We will explore the reciprocal relationships between FUS assembly and synaptic activity in neurons under optogenetic control (Aim 4). We will use novel imaging methods to determine whether FUS assemblies are secreted and can be detected in CSF (Aim 5). This work has major implications for neurobiology and medicine.