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Funders:
The Wellcome Trust

Results

The Interplay Between Need and Response: An ethnographic multi-stakeholder response analysis to mental distress in post-disaster urban Nepal 10 May 2016

‘Mental health disaster’ humanitarian efforts and resources are largely being spent on addressing post-traumatic stress disorder (PTSD) despite the lack of agreement on the public health validity and utility of the diagnosis. The usefulness of these efforts and investments is widely debated. Less amount of work has looked at the nature of the relationship between mental health care need(s) and response(s) in these settings. Focusing on post-disaster urban Nepal, this project explores how different stakeholders understand the mental health needs of the population, how they are responding to these and what is the interplay between the need(s) and response(s). The main research question is: How do mental health ‘need(s)’ and ‘response(s)’ shape and re-shape each other? The clinical/healing, humanitarian and family/community contexts will be studied ethnographically during 12 months of fieldwork in Lalitpur (Nepal). Qualitative methods of investigation will be used, including semi-structured interviews, focus groups, case studies and free-listing. The key goals are to 1) elucidate points of convergence and divergence in conceptualizations of mental distress amongst different stakeholders 2) to inform policy and provide suggestions for service delivery that could lead to more meaningful outcomes 3) help avoid inappropriate, wasteful and/or harmful ways of addressing ‘mental distress’.

Amount: £84,061
Funder: The Wellcome Trust
Recipient: University of Edinburgh

An Empirical Study of Children and Adolescents' Perspectives on Testing Minors for their Genetic Predisposition to Psychiatric Disorders 10 May 2016

Predictive genetic testing for psychiatric disorders could help prevent or delay the development of debilitating conditions. However, the complex inheritance, incomplete penetrance, and variable expression in the genes underlying mental disorders make such testing a relatively poor predictive instrument. Empirical studies investigated the socio-ethical impacts of such testing from the perspectives of adult patients, family members, psychiatrists, and geneticists, who highlighted the risk of promoting a deterministic stance on psychiatric conditions, of discrimination against and stigma of the individuals tested, and the potential negative effects on family relationships. However, no systematic study has investigated minors’ perspectives. This is an important gap in the debate, as minors are likely to be the main target of psychiatric genetic testing. Therefore, the aim of my research is to investigate children and adolescents’ perspectives on testing minors for their genetic predisposition to psychiatric disorders. My research will assess whether their concerns confirm those expressed in the academic literature and it will provide a more inclusive account of the public’s opinions, thereby promoting an ethically robust application of scientific discoveries in this field. I will conduct a systematic review of the ethics literature on psychiatric genetic testing in minors and a systematic qualitative interview study.

Amount: £93,065
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £264,775
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Role of the Adaptor Protein-2 Sigma Subunit (AP2σ) in Calcium Homeostasis 30 Sep 2016

G-protein coupled receptors (GPCRs) facilitate cellular responses to extracellular stimuli, and GPCR mutations result in many diseases, including endocrine disorders. Mutations of the calcium-sensing receptor (CaSR), a pivotal GPCR in calcium homeostasis, resulting in loss-of-function or gain-of-function cause familial hypocalciuric hypercalcaemia type-1 (FHH1) and autosomal dominant hypocalcaemia type-1 (ADH1), respectively. FHH and ADH are genetically heterogeneous, and loss-of-function or gain-of-function mutations of the G-protein-alpha11 utilised by CaSR, cause FHH2 and ADH2, respectively; while loss-of-function mutations of adaptor protein-2 sigma subunit (AP2sigma), which is critical for clathrin-mediated endocytosis, cause FHH3. To date, the reported AP2sigma mutations, which cause only FHH3 but not ADH, all affect residue Arg15 and impair CaSR signalling and trafficking. However, the Thakker group have recently identified seven other AP2sigma variants (Arg3His, Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu120Gly), and my goal is to determine the roles of these AP2sigma variants in calcium homeostasis by: 1) Characterising their structural-functional relationships by in vitro studies that assess effects on three-dimensional models and on CaSR signalling and trafficking pathways. 2) Determining in vivo phenotypes of AP2sigma mutations by generating knock-in mouse models, using CRISPR-Cas. 3) Assessing pharmacological effects of drugs, e.g. velcalcetide, using above AP2sigma in vitro and in vivo models.

Amount: £348,449
Funder: The Wellcome Trust
Recipient: University of Oxford

Health Priorities in Resource Limited Settings 30 Sep 2016

Liverpool Clinical PhD Programme: Health Priorities in Resource Limited Settings

Amount: £74,797
Funder: The Wellcome Trust
Recipient: University of Liverpool

Multi-modality imaging assessment of cerebral small vessel disease biomarkers after stroke due to spontaneous intracerebral haemorrhage 30 Sep 2016

BackgroundStroke due to spontaneous intracerebral haemorrhage (ICH) annually affects ~3.4 million adults worldwide.Approximately 85% of ICHs are thought to be caused by cerebral small vessel diseases (SVDs), such asarteriolosclerosis and cerebral amyloid angiopathy (CAA), which are often studied individually rather than incombination. While SVDs are definitively diagnosed at autopsy, advanced neuroimaging can demonstratebiomarkers and features indicating SVDs, and could help identify their contributions to ICH occurrence,severity and outcome ante mortem.HypothesisMultiple imaging biomarkers of SVDs on one or more imaging modalities will be superior to singlebiomarkers for detecting and distinguishing SVDs underlying ICH, and determining outcome.Key methods/goals1. I will use CT and MR imaging from an on-going inception cohort study of ICH to assess imagingbiomarkers of SVDs, and correlate these with clinical, genetic and pathological findings.2. I will investigate the feasibility and utility of identifying CAA using flutemetamol, in vivo with MRpositronemission tomography, and ex vivo with autoradiography/autofluorescence studies on braintissue.3. I will compare the association between MR-PET imaging phenotype in different types of ICH (lobarand deep).

Amount: £223,001
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Hepatitis B in Malawi: Epidemiology and determinants of fibrosis and virological expression 30 Sep 2016

Hepatitis B (HBV) is highly endemic in Malawi with an estimated seroprevalence of 7.5 (95% confidence interval 5.5-10.6). Among a recently described HIV/HBV co-infected cohort in Blantyre, particularly aggressive virological expression was observed compared to other sub-Saharan African cohorts, with high rates of HBV replication, HBe antigen expression, and poor responses to lamivudine. There are very limited data on the epidemiology and natural history of HBV from sub-Saharan Africa. Current understanding of the environmental, viral and host factors responsible for determination of disease severity are derived largely from Asian and Western cohort studies. The aim of this project is to determine the determinants of severity of HBV among a community study in Blantyre, Malawi. Random adult participants in an observational community-based study of typhoid seroincidence (n=9700) will be screened for HBsAg and 250 positive and 125 negative controls will be recruited. An inpatient cohort of people with liver disease will also be screened for HBV. Markers of HBV virological expression, transient elastography to determine liver fibrosis, questionnaires for lifestyle factors and next generation genome sequencing of HBV and host will be undertaken to determine the relative contribution of environmental, host and viral genetic factors to the development of fibrosis.

Amount: £400,000
Funder: The Wellcome Trust
Recipient: University of Liverpool

The effect of hypoxia-inducible factor 2 activation on macrophage function in Idiopathic Pulmonary Fibrosis. 19 Nov 2015

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease causing hypoxemia and fatal respiratory failure. Incomplete understanding of pathogenic mechanisms hinders the development of effective therapies. Sudden deterioration due to acute exacerbations (AE-IPF), often triggered by infection, lead to rapid deterioration in the patients condition, often proving fatal. Lung macrophages are long-lived, highly oxygen sensitive, cells implicated in IPF pathogenesis. Their phenoty pe dictates their function. In IPF, alveolar macrophages (AM) are predominantly alternatively-activated (AAM). As IPF progresses, hypoxia activates hypoxia-inducible factors (HIF), with HIF-2, rather than HIF-1, found mainly in AAM. HIF-2 deletion in neutrophils improves infection resolution, however the role of HIF-2 in macrophage function and bactericidal activity, particularly in IPF, remains unknown. I aim to determine the role of HIF-2 in macrophages in IPF using mouse models of fibrosis, as well as human macrophages from IPF sufferers. I will also investigate the effects of HIF-2 activation in macrophages on their metabolic function and their phenotype. In order to assess the role of macrophages in AE-IPF, I will investigate the phenotype plasticity, as well as the bactericidal capacity of AM from mice undergoing lung fibrosis models, as well as from human IPF patient samples.

Amount: £325,999
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Identification of novel subtype of monogenic diabetes by excluding Type 1 diabetes using a polygenic risk score 19 Nov 2015

Background: Finding the genetic aetiology of monogenic diabetes has had profound scientific and clinical implications. Currently, novel subtypes of monogenic diabetes are identified by studying patients who have a clinical phenotype of known subtypes of monogenic diabetes but lack mutations in the known genes. This approach is biased: lacking ability to identify previously undescribed phenotypes. In non-obese children, Type 1 diabetes (T1D) is the only alternative diagnosis to monogenic diabetes . Therefore potential novel monogenic subtypes can be found by excluding T1D by presence of autoantibodies, but this approach is limited as autoantibodies are absent in 10-20% of T1D patients. Preliminary Data: I showed a T1D-genetic risk score (T1D-GRS), based on T1D associated common genetic variants, in the neonatal period(<6months) identifies individuals with monogenic diabetes by robustly excluding T1D. Key goals: I will genotype the T1D-GS in large cohorts of slim patients with childhood -onset diabetes from the UK (n=5000), and Turkey (n=700) to identify patients in whom T1D is highly unlikely (T1D-GS <1st centile of T1D) so monogenic diabetes highly likely. I will perform whole-genome-sequencing on these patients to find novel genetic aetiologies. I will perform detailed phenotyping of the individuals with confirmed novel genetic aetiologies to understand the associated biology.

Amount: £415,179
Funder: The Wellcome Trust
Recipient: University of Exeter

Avoiding on-target off-tumour toxicity in cancer immunotherapy. 19 Nov 2015

Chimeric antigen receptors link MHC-unrestricted antigen specificity with T-cell signalling, facilitating potent and regulatable antigen-specific cancer recognition and killing. Clinical trials of CAR gene modified T-cells show unprecedented clinical responses, with the major limitation of on-target off-tumour toxicity due to expression of most cancer antigens on some normal tissues. In my Wellcome clinical training fellowship I identified a novel method of avoiding such toxicity by designing CA Rs for use in gdT-cells. These gdT-CAR cells combine innate killing limited to sites of cancer or injury with CARs providing co-stimulation to overcome the immunoinhibitory tumour microenvironment. I demonstrated proof of concept using two model antigens, GD2 and CD33, applicable to solid cancers (e.g. neuroblastoma) and myeloid leukaemias (e.g. AML) respectively. In my fellowship I will develop this by: 1) Identifying mechanism and relative efficacy of different co-stimulatory CAR endodomains in gdT cells 2) Investigate selectivity of co-stimulatory CARs in gdT against acute myeloid leukaemia compared with healthy blood cells bearing the same tissue antigen. 3) Investigate the use of mass cytometry for high-dimensional signalling analysis to inform CAR design. Efficacy, toxicity and mechanism will be assessed in a staged manner using cell lines and primary tissue.

Amount: £275,672
Funder: The Wellcome Trust
Recipient: University College London

Dissecting the neural components of the hippocampal cognitive map 05 Jul 2016

The existence of place, directional, boundary and grid cells in the rat hippocampal formation provides strong evidence that this part of the brain functions as a cognitive map. This theory suggests that the hippocampal formation contains map -like representations of familiar environments which enable the animal to identify its current location together with desirable and undesirable locations and to generate the vectors to move towards or away from these. I propose to use novel behavioural tasks, high-density extracellular recording probes, 2-photon imaging, and pharmacological and optogenetic manipulation of cell activity to explore in-depth the properties of these spatial cells and the role of different components of the hippocampal formation in spatial memory and navigation. Specifically I will address the following questions: How well does the activity of place, head direction and grid cells correlate with the animal’s perception of the different aspects of space and which cells are important in supporting navigation to an unmarked goal? What are the relative roles of external landmarks versus internal path integration signals in determining the firing of place cells? Do the l grid cells signal distance travelled in a particular direction or something else such as the shape of the environment?

Amount: £2,837,189
Funder: The Wellcome Trust
Recipient: University College London

Activity-dependent plasticity of long-range sensorimotor connectivity. 02 Dec 2015

This proposal will consider when and how activity-dependent plasticity of long-range brain connections occurs, and will assess its behavioural significance. The programme will include work ranging from cellular level studies of the underlying biology in rodents, and basic science studies in human volunteers, through to proof of principle trials in clinical populations. The proposal includes the following work packages: 1. Manipulating activity These projects use neurofeedback to alter hu man brain activity in order to test whether modulating activity in specific sensorimotor circuits can produce rapid and bidirectional changes in brain connections and change behaviour. 2. Manipulating behaviour. This programme will test whether reduced limb use results in altered functional and structural connectivity. 3. Underlying biology Studies in transgenic rodents will assess whether myelin change contributes to plasticity of brain connections. Secondary questions concern the role of sleep in observed changes in brain connections and behaviour. 4. Boosting plasticity of brain connections for rehabilitation In our final work package, we will apply principles established from the basic science programme described above to stroke rehabilitation. First, we will assess whether neurofeedback can be used to rebalance motor-related activity after stroke. Second, we will test whether improving sleep quality after stroke can affect rehabilitation outcomes, due to the importa nce of sleep for consolidation of motor learning.

Amount: £2,481,628
Funder: The Wellcome Trust
Recipient: University of Oxford

Epigenetic inheritance: establishment and transmission of specialised chromatin domains 05 Apr 2016

Specialized chromatin domains provide platforms that mediate fundamental cell and developmental functions. The histone H3-variant CENP-A chromatin directs assembly of kinetochores at specific chromosomal locations to enable accurate chromosome segregation. Heterochromatin renders potentially harmful repetitive elements inert and silences genes during development. Regional fission yeast centromeres provide an excellent paradigm for unwieldy metazoan centromeres. Our analyses indicate that H3K9-methylation-dependent heterochromatin and CENP-A assemble upon non-conserved elements at centromeres whose chromosomal location is preserved in related Schizosaccharomyces species. My predominant goal is to understand the conserved signals and mechanisms that distinguish these non-conserved centromere sequences from other genomic loci, as well as the epigenetic mechanisms that result in the establishment of heterochromatin and CENP-A chromatin, and their stable mitotic and transgenerational transmission. I aim to determine: 1. How specific signals associated with centromere DNA, RNA, chromatin and RNAPII transcription direct assembly and maintenance of heterochromatin and CENP-A specialised chromatin domains. 2. The influence that positioning at the nuclear periphery exerts on heterochromatin domain robustness and the establishment of CENP-A chromatin on adjacent centromere DNA. 3. The potential for sporadic heterochromatin formation across the genome to generate phenotypic heterogeneity in genetically identical wild-type cells thereby increasing adaptability to environmental changes.

Amount: £3,046,873
Funder: The Wellcome Trust
Recipient: University of Edinburgh

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
Amount: £15,000
Funder: The Wellcome Trust
Recipient: University of Birmingham

Public Engagement Provision 31 Dec 2015

Despite host shifts being a major source of emerging infectious disease, we have much to learn about why hosts vary in their susceptibilities to novel pathogens and how viruses evolve in new hosts. The first goal of this fellowship is to understand what factors affect the ability of a virus to infect a novel host. I will break the infection process down into different steps to test whether differences in susceptibility are due to the ability of the virus to: bind, enter, replicate in, and exit h ost cells. I will then examine whether the ability of the virus to suppress the host immune response can determine whether it can infect novel hosts. I will investigate the relative importance of environmental versus host-genetic factors in determining the success of host shifts by determining how susceptibility changes with temperature. Next I will use viruses experimentally evolved in different species to examine how viruses adapt to host species, and what consequences this has on their abilit y to infect further hosts. Finally, I will evolve viruses in alternating hosts, using closely or distantly related species, to examine how host breadth affects the potential of a virus to infect a range of novel hosts.

Amount: £31,100
Funder: The Wellcome Trust
Recipient: University of Exeter

Transitional States: Hormones at the Crossroads of Art and Science 31 Aug 2016

Provision for Public Engagement Transitional States: Hormones at the Crossroads of Art and Science

Amount: £50,115
Funder: The Wellcome Trust
Recipient: University of Lincoln

Public Engagement for the Thailand Major Overseas Programme 2015 - 2020 30 Apr 2016

The mission of the Wellcome Trust Thailand Major Overseas Programme is to carry out targetedclinical and public health investigations, using the best science, to provide appropriate andaffordable interventions which produce measurable improvements in the health of resource-poorpopulations in the tropics. Over the past 35 years the Programme has built substantial clinicaland laboratory research capabilities, deployed across a well-integrated network of strategicallyplaced permanent study sites and research units in seven countries across Asia and Africa. Wewill use this expertise and research capacity to tackle the epidemiology, diagnosis,pathophysiology, treatment, prevention, and, in the case of malaria, elimination of thoseunderstudied infectious and nutritional diseases that cause significant morbidity and mortality inthe populous rural tropics. In doing so we will strengthen local research capacity, a majorobjective of the programme, and build lasting south-south research collaborations with ourpartners across the developing world. We will inform health policy, change clinical practice, andmake a global impact on mortality from tropical infectious disease.

Amount: £618,799
Funder: The Wellcome Trust
Recipient: University of Oxford

Everyday Cyborgs: Stories from Inside Out 31 Oct 2015

'Animal, Machine and me' is a sociological investigation into modern practices that repair and replace the human heart serves as a study in its own right but also one that has implications for developments in xenotransplantation and implantable technologies more generally. Utilising a case study approach three areas have been identified as contributing to the construction of stories or biographies of the implanted heart. These are 1) decision-making processes around porcine, bovine or mech anical aortic heart implants 2) recipient experiences of ICDs and 3) TAHs as an example of technological development in the area of whole organ replacement. A multi-method approach is indicated and will be conducted at various sites in the UK and the US. Envisaged outcomes are: increasing understanding of both clinical and non-clinical factors influencing the choice of animal or mechanical implants; reasons for psychosomatic side-effects in ICD patients and a review of the various factors invo lved in developing TAHs. There are therefore two transitions under scrutiny; the material from animal to human and the technological from implant to device to whole organ. Future research will seek to add an epidemiological strand by investigating the political economy of implants in developing countries

Amount: £35,050
Funder: The Wellcome Trust
Recipient: University of Edinburgh