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LMIC Travel Scholarships for Global Climate and Health Forum 30 Sep 2018

The Global Climate and Health Forum is a one-day, high-level convening of global climate and health leaders designed to mobilize stronger health sector engagement in and commitments to climate action. The Forum will bring together 250 leaders from national and local governments, health systems, public health agencies, civil society, and international organizations to build the community of climate and health professionals, strengthen collaboration across sectors, and raise the health voice for climate action. The Forum will be held at the University of California, San Francisco on September 12th, 2018. The Forum is an affiliate event of the Global Climate Action Summit, and co-hosted by the UCSF Global Health Group, Health Care Without Harm, Global Climate and Health Alliance, and US Climate and Health Alliance. In order to make the Forum a truly global event, it is imperative that the Forum includes speakers and participants from low- and middle-income countries who are leading climate mitigation, adaptation, and resilience work in the most vulnerable regions and communities. Funding from the Wellcome Trust will be used to support five travel scholarships for participants from the global South, including all registration, travel, accommodation, and event-related expenses.

Intra-Africa Mobility Initiative on Science, Language and Culture 30 Sep 2018

The Alliance for Accelerating Excellence in Science in Africa (AESA), Wellcome Trust (WT) and the Institut Pasteur International Network propose a researcher mobility program which would support African researchers (who share our ambition) to break down language and cultural barriers that impede greater African research collaboration in the biomedical and health sciences.Over the next 5 years, we aim to support at least 50 researchers to undertake mobility favoring the enhancement of their scientific careers while also increasing the understanding and interconnections of the African research community within different cultural and linguistic environments. Where language is the barrier we will look for flexible ways of providing support and funding language training. The program will aim to; Strengthen scientific collaboration between Anglo and Francophone speaking African scientists Build language skills/capabilities in English and French among African scientists Improve cultural understanding between English and French speaking African scientists The program will build out from the DELTAS and H3Africa researcher communities and the Institut Pasteur network, Our indicator of success will be; By December 2020, 50 African researchers will have experienced the mobility program and report positively on breaking down language and cultural barriers to research.

Amount: £198,662
Funder: The Wellcome Trust
Recipient: African Academy of Sciences

C. elegans – a model system to study causation in the microbiome-gut-brain axis 06 Sep 2018

Metagenomic approaches are generating a long list of health and disease states associated with the microbiome (the microbes inhabiting our digestive tract) but without mechanistic understanding. The challenges arise from the enormous complexity of the microbiome, including genetic, environmental and dietary variations, microbe-microbe interactions, and the cost associated with studying the microbiome using murine models. If the field is to move beyond association, simple, well-controlled and cost-effective models allowing unbiased high-throughput studies are needed. The nematode C. elegans is a genetically tractable model, ideally suited for mechanistic and causative studies of host-microbiome and microbe-microbe interactions shaping host physiology and metabolism. Aims: 1) Establish an experimental microbiome in C. elegans based on strains from the human microbiome associated with health, disease and ageing 2) Generate fluorescent labelled bacterial strains and perform real-time imaging of gut colonisation 3) Characterise the effects of the experimental microbiome on the microbiome-gut-brain axis during ageing The experimental microbiome in C. elegans will be an important contribution to the field, complementing existing models. It will allow me to establish important collaborations, form a basis for my future research and address one of the most important questions of modern biology: the effects of the microbiome on host physiology.

Amount: £99,905
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Biomaterial-based delivery of neurotrophic factors to the Parkinsonian brain 31 May 2018

The concept of cellular brain repair for Parkinson's disease is relatively simple - if brain cells die in this condition, then it should be possible to replace these cells through transplantation of healthy cells back into the brain. Over the past three decades, numerous animal studies and several clinical trials in human patients have shown that this concept has significant potential for repairing the brain affected by Parkinson's disease. However, poor survival of the healthy cells has limited the widespread roll-out of this cellular reparative approach to patients. Biomaterials, that is, materials that have been engineered to interact safety with living tissue for therapeutic purposes, have the potential to improve such cellular reparative therapies for Parkinson's disease. Specifically, injectable biomaterials gels have the potential to significantly improve cell survival by providing a physical scaffold and pro-survival environment for the implanted cells. Thus the aim of this proposal is to determine if biomaterial hydrogels can be used to improve cellular reparative therapies for Parkinson’s disease using animal models of the condition. We will specifically investigate the beneficial effect of biomaterials on stem cell-derived neuron cell transplantation approaches.

Optimising antimalarial treatments in sub-Saharan African children: reducing the burden of malaria mortality 31 May 2018

Sub-Saharan Africa accounts for 99% of all reported malaria cases. Children under five years are often the most vulnerable, accounting for 71% of all malaria deaths (WHO, 2017). This can be attributed to the low immunity in children which increases their vulnerability to malaria infections. Testing of drugs in children can be difficult due to ethical concerns. However, advances in pharmacokinetics (the study of how the body processes drugs) has given rise to a novel approach, which enables the simulation (in virtual clinical trials) of many clinical subjects, each possessing a unique subset of physiological parameters. Results from a previous research on pregnant women conducted by our group using the same approach was found to provide an effective dosage regimen (Olafuyi et al, 2017). In this project, we will adapt the pharmacokinetic approach to examine dosage regimen in children using piperaquine (antimalarial drug). We will also address potential drug interactions in patients co-infected with HIV, where anti-retroviral drugs can lead to the enhanced degradation of piperaquine. The study will look at data and its impact on cohorts and recommend an appropriate dosage regimen for children in sub-Saharan Africa under malarial only and malaria-HIV co-infection, which will help reduce anti-malarial resistance.

Amount: £0
Funder: The Wellcome Trust
Recipient: Aston University

Effects of sex on metabolic homeostasis in old age 31 May 2018

The main aim of our research is to determine the differences in the lifespan and physiology of male and female Drosophila melanogaster in response to increased levels of sugar (sucrose) in the diet. Current human diets are detrimental to health and obesogenic. The health outcomes are dependent on the sex of the individual, however the molecular and physiological mechanisms are not understood. The results of our study will help establish a Drosophila model that can be used to understand how nutrition and sex interact, which might contribute to a healthier lifestyle choices in humans leading to healthy ageing. The effects of diet on lifespan and diet-induced obesity of the two sexes will be recorded, as well as the feeding behaviour using the proboscis extension assay and blue-food assay. Gut morphology/function will also be examined since the gut appears to underlie the different response of the sexes to increased dietary protein. In particular, we will focus on age-induced hyperplasia by determining the number of proliferating cells (stained with anti-phospho-Histone 3). We will also monitor gut function by assessing the leakiness of the gut using a blue food. Finally, statistical analysis using suitable regression models will be performed in R.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

PhD Grant Proposal 30 Sep 2018

Older people are often classed as either experiencing ‘normal’ cognitive ageing, or ‘pathological’ cognitive ageing as a result of diseases such as Alzheimer’s (AD). However, these classifications fail to reflect the spectrum of cognitive decline that is experienced as we age. Age-related cognitive decline is a hugely important health problem; it has a profound impact on quality of life, increases the risk of depression and may herald dementia. Because of this, it is important to investigate what influences how well we age cognitively. Age itself is the biggest risk factor for cognitive decline. The comprehensive causes and mechanisms of ageing are not fully understood but we do know that the process is closely integrated with inflammation – the body’s immune response to injury or irritants. Although recently receiving significant attention, the precise cause-and-effect relationship between inflammation and cognitive ageing has not yet been fully explored. Using different techniques, this project will investigate the role of inflammation in cognitive ageing, and whether the process can explain why some people are more resilient than others. Understanding the differences in individual’s cognitive decline is critical to developing interventions to prolong cognitive health and to gain insight into diseases of cognition such as AD.

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

Investigating the immunomodulatory effects of extracellular vesicles derived from mesechymal stromal cells 31 May 2018

My proposed hosting group has shown that mesenchymal stromal cells (MSCs) ameliorate kidney injury in mice through paracrine effects.Their preliminary work suggests that the MSCs are entrapped in the lung following intravenous administration and mostly die within 24 hours. Host macrophages are attracted to the MSCs and are stimulated to upregulate the anti-inflammatory cytokine, IL10, which suggests they are being polarised towards an anti-inflammatory phenotype (i.e. to M2 macrophages). The main aim of my project is to explore whether extracellular vesicles (EVs) released by the MSCs are responsible for mediating their immunomodulatory effects. Specifically, I will investigate whether the EVs polarise macrophages towards an M2 phenotype. The first objective will be to use a co-culture model comprising human bone marrow-derived mesenchymal stromal cells (BM-MSCs), which have already been shown to polarise macrophages to an M2 phenotype. The BM-MSCs will be co-cultured with human macrophages using a transwell culture system, and the ability of the BM-MSCs to polarise the macrophages to M2 will be investigated using flow cytometry and quantitative reverse transcriptase PCR (qRT-PCR) to determine the levels of M1 and M2-specific markers. The effect of BM-MSC-derived EVs on macrophage polarisation will then be tested.

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

Diagnostic needs for Antimicrobial Resistance 30 Sep 2018

Despite various calls for action and some initial work to map diagnostics for AMR, no authoritative list exist for commercially available (or under development) in vitro diagnostics for antimicrobial resistance (AMR in vitro diagnostics). Similarly, Target Product Profiles to guide the development of these diagnostics are also lacking. Multiple stakeholders including the diagnostic industry, academia and NGOs have stressed the need to address this gap. In response to this scenario, WHO will coordinate the mapping of diagnostic tools (both existing and in development) to address antimicrobial resistance; identify gaps and establish a WHO R & D priority list for AMR in vitro diagnostics. Target Product Profiles for high priority AMR in vitro diagnostics will also be developed, published and disseminated to relevant stakeholders.

Amount: £470,764
Funder: The Wellcome Trust
Recipient: World Health Organization, Switzerland

Hypothalamic development from self-organising progenitors 17 Jul 2018

The hypothalamus governs homeostasis of core body function throughout life but its development remains enigmatic. Our recent unpublished work reveals that a small region at the ventral midline of the embryonic neural tube intrinsically develops into the three classically defined domains of the adult basal hypothalamus, including a domain that contains stem cells. This suggests an unprecedented mechanism of self-organisation exists within ventral midline hypothalamic progenitor cells that we will define in this application. Our objectives are to: 1. Identify when self-organising hypothalamic progenitors are induced, and the tissues required 2. Determine the minimum cell number that can self-organise into the hypothalamus 3. Understand if self-organisation involves a self-renewing multipotent stem cell 4. Characterise cell behaviour in self-organising hypothalamic progenitor cells 5. Understand the molecular basis of hypothalamic self-organisation These studies will reveal mechanisms that orchestrate hypothalamic development. They will provide insight into the extent to which hypothalamic stem/progenitor cells can adapt over time and generate/regenerate new cell types. Finally, they may provide insight into the construction of hypothalamic organoids, an important future tool to understand the function and sensitivity of this small, intricate and hard-to-access region of the brain.

Amount: £1,129,365
Funder: The Wellcome Trust
Recipient: University of Sheffield

Statistical Analysis of the Type 6 Secretion System in Pseudomonas Aeruginosa 30 Sep 2018

Pseudomonas aeruginosa is a Gram-negative bacterium that is a leading cause of many hospital borne infections. In particular recent research has identified the Type 6 Secretion System (T6SS) present in P. aeruginosa and has focused on the structure and mechanism of the system. This highly complex system allows P. aeruginosa to accurately penetrate adjacent cells and thus insert an array of toxins which can cause cell death or disrupt cellular pathways. Building on this work we would like to understand the T6SS from a statistical perspective. Understanding the spatial distribution and dynamics of the T6SS along the cell membrane of P. aeruginosa are amongst a number of different questions we hope to explore in this project. To achieve these targets we will use fluorescently tagged components of the T6SS mechanism as well as confocal microscopy of living P. aeruginosa, thus allowing for 3-dimensional reconstruction. These biological questions will be answered using a variaty of quantitative approaches. To extract important information from the image data a number of imaging and video preprocessing methods will need to be applied. After preprocessing the this data will be analysed using a variaty of statistical methdologies in order to provide a quantitative description.

Amount: £0
Funder: The Wellcome Trust
Recipient: Imperial College London

Active Inference and Optimal Decision-Making 30 Sep 2018

Depression is strongly associated with a decline in cognitive function, and is seen in a high number of elderly individuals. It has been suggested that there is a strong epidemiological link between a personal history of depression and an increased risk of developing Alzheimer’s disease in later life. The key aim of this project is to use models of learning and decision-making to better link behavioural characteristics of these two psychiatric illnesses to their brain circuit substrates. We aim to reveal model-based behaviours and brain circuits that are shared with depression and different dementia profiles, including Alzheimer’s disease. We will use an adapted version of a pre-existing video game environment to examine activation of the dopaminergic midbrain, using fMRI. We will look specifically at reward prediction errors, and precision, i.e. the degree of confidence in the action an individual takes. By describing these behaviours using computational models, we hope to provide more accurate descriptions of human behaviour, the causes of such behaviours, and the specific brain regions and neural circuits that these behaviours are linked to. This may lead to earlier diagnosis of such psychiatric illnesses; therefore patients can undergo treatments earlier on in the disease progression.

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

Wellcome Fellowship on the Clore Leadership Programme 2019/20 - 2020/21 30 Sep 2018

We are applying for two Wellcome Fellowships on the Clore Leadership Programme, to join cohorts of exceptional cultural leaders who can engage and stimulate new thinking and development across a wide range of audiences and sectors, including health, research and wellbeing by combining perspectives from the arts, humanities and social and medical sciences. The final focus of the Fellowships will be determined in discussion with the Wellcome Trust and in line with its priorities. The Fellowship is a bespoke professional development opportunity responding directly to the training needs of the individual, which includes residential courses, coaching, mentoring, a secondment, and access to a personal training budget. Our ambition is to support professional development and create resilient and authentic leaders, who can support their peers and the sector, and can ensure that the arts and culture are having the most positive possible impact on civic life. By offering the Wellcome Fellowships in 2019/20 and 2020/21, we aim to support the development of leaders who will encourage their audiences, collaborators and the wider public to access research and innovation, and establish better dialogues between the public and the scientific community through culture.

Amount: £60,000
Funder: The Wellcome Trust
Recipient: Clore Leadership Programme

Investigation into the role of RBM8A/Y14 in the development and function of megakaryocytes and platelets using a human pluripotent stem cell model of haematopoiesis 30 Sep 2018

Platelets are small blood cells, which cause blood to clot, preventing bleeding after injury. They are produced by megakaryocytes, large cells in the bone marrow. In people with low platelet counts (thrombocytopenia), life-threatening bleeding occurs spontaneously or after injury. Studying platelet and megakaryocyte development and function is important in understanding a) diseases causing thrombocytopenia, such as genetic disorders and other conditions, particularly cancer (and chemotherapy) and b) strokes and heart attacks, where platelets are excessively activated, forming clots that block vessels. Using stem cells (special cells capable of becoming any cell type) derived from adult skin or blood samples we grow & study megakaryocytes and platelets in the laboratory. We study a rare genetic disease, Thrombocytopenia with Absent Radii (TAR) syndrome, in which babies are born with very few platelets and abnormal bone formation (particularly the radius in the forearm). Our group discovered the cause of TAR, due to abnormalities in a gene called RBM8A, which helps cells control what proteins are produced; however precisely why this causes TAR is unclear. We believe our research will uncover the mechanism of this condition, helping to treat patients with TAR and improve wider understanding of how megakaryocytes & platelets develop and function.

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

RC Psych Integrating Neuroscience Project (Phase 2) 30 Sep 2018

The Royal College of Psychiatrists has been proud to partner with The Wellcome Trust on a co-funded project with the Gatsby Foundation between 2016 and 2018 through the first phase of this project. The ‘Integrating Neuroscience’ project has achieved significant success under the leadership of the President of the RC Psych, guided by an internationally-renowned Neuroscience Commission which was established as a result of this partnership. The project continues to achieve the intended outcomes within budget and on time. Following discussions with both The Gatsby Foundation and The Wellcome Trust, we propose the renewal of this partnership for a further three years. The changes we would like to see as a result of this next phase are: That the sustainability of the project is ensured so that it becomes part of core College business with a curriculum lead funded by the RC Psych. That the recommended changes to the psychiatric curriculum will have been implemented and tested. That we will have secured external funding to assess the impact of these changes. That we will have built a community of neuroscientists and neuro-psychiatrists who will curate the knowledge base and drive collaboration across the whole sector.

Amount: £164,899
Funder: The Wellcome Trust
Recipient: Royal College of Psychiatrists

Investigation of pro-regenerative mesenchymal subpopulations during liver regeneration using a single cell RNA sequencing approach 30 Sep 2018

Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide. The liver has a remarkable ability to regenerate following injury, however in many cases of CLD this regenerative capacity is overwhelmed. Currently the only effective treatment is liver transplantation but demand for donor organs greatly outstrips supply. New therapies are urgently required. Liver regeneration involves a complex interplay between multiple cell types, including a family of cells called mesenchymal cells. Whilst traditionally, the role of mesenchymal cells was more often studied in the context of liver fibrosis (scarring), recent studies have shown that these cells are also important during liver regeneration. Initial experiments in the Henderson lab, using a cutting-edge technology called single cell RNA sequencing (which allows the sequencing of genes in single cells), has shown that mesenchymal cells, rather than being one family of cells with similar function, are actually very varied in terms of their function, performing many different, important roles within the liver. I will use this powerful technique to identify the pro-regenerative mesenchymal cell subpopulations responsible for driving liver regeneration. Using this information, we hope to design new treatments to harness specific cellular subsets to drive liver regeneration in patients with CLD.

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

Ethical Considerations of Alternative Clinical Trial Methods and Designs: Challenges and Opportunities 19 Feb 2018

During the Global Forum on Research Bioethics (GFBR) a critical and rigorous evaluation was carried out with respect to alternative designs and methods for conducting clinical trials. GFBR answered several questions related to the ethical implications of these alternative designs and methods, improved the understanding of their elaboration, and allowed attendees to consider the types of situations and research questions in which it may be more efficient and perhaps necessary to employ alternative clinical trial designs. However, GFBR also showed that alternative clinical trial methods and designs are well-known in high-income countries, but that there is little knowledge or literature in low- and middle-income countries. The Network of Committees for Ethics in Research (RECEIH) in Cali, with the support and expertise from several Latin American participants from GFBR, proposes the implementation of such a workshop in Colombia. This workshop will strengthen the roles and analytical skills of researchers, regulatory institutions, and CIE (Institutional Ethics Committee) members to make reasoned, rigorous, and critical reviews of clinical trials that use alternative designs and methods, in addition to ensuring their implementation according to the highest ethical standards.

Specialised Ribosomes – Does KSHV modulate ribosome composition 30 Sep 2018

Historically, ribosomes have been viewed as unchanged homogeneous units with no intrinsic regulatory capacity for mRNA translation. Recent research is shifting this paradigm of ribosome function to one where ribosomes may exert a regulatory function or specificity in translational control. Emerging evidence has identified heterogeneity of ribosome composition in specific cell populations, leading to the concept of specialised ribosomes. Specialised ribosomes may therefore exhibit control and regulation over the translation of specific mRNAs, resulting in a substantial impact on how the genomic template is translated into functional proteins. Due to the emerging concept that cells can control the composition of ribosomes to regulate protein expression, it would seem highly likely that viruses could also manipulate host cell ribosome compositions to enhance the production of viral proteins. We have quantitative proteomic and ribosomal profiling data suggesting Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates ribosomal biogenesis. Firstly, we will investigate changes in composition and stoichiometry of proteins within the ribosome, driven by KSHV. We will isolate ribosomal complexes by tandem affinity purification, during KSHV infection and analyse changes by LC-MS/MS and cryo-EM. We will elucidate how these changes exert ribosome-mediated specificity to promote KSHV lytic infection using a number of cellular and molecular techniques.

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

Gene Therapeutic Strategy for Autosomal Recessive Spastic Paraplegia Arising From Mutations in SPG47 31 May 2018

Hereditary spastic paraplegias (HSPs) are a family of progressive lower-limb spasticity disorders characterized pathologically by degeneration in the corticospinal and spinocerebellar tracts. Spastic paraplegia type 47 (SPG47) is a subtype of HSP, caused by recessive mutations in the AP4B1 gene, leading to a significant reduction in the transcript protein levels. The gene codes for a subunit of Adaptor protein complex 4 (AP4), an essential intracellular trafficking protein in neurones. A loss-of-function hypothesis for SPG47 is backed by substantial emerging evidence, as mutations in all the other subunits of the AP4 complex disrupt the protein's normal and cause a very similar clinical presentation to that of SPG47. Gene therapy aimed at restoring AP4B1 protein expression therefore represents a rational therapeutic approach to ameliorate the disease phenotype. This project aims to design therapeutic vectors (AAV9 and AAV-PHP.B.) to express human AP4B1 gene under Chicken Beta Actin promoter. It also aims to evaluate their in vitro efficacy in cortical neurons isolated from AP4 ß-/- knockout mouse model and AP4B1 KO HeLa cell lines. If successful, the vectors can be tested in the future in animal models and eventually in clinical trials, aiming to treat SGP47 and improving patients’ quality of life.

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

Quantifying the influence of wind on mosquito flight and consequences for malaria transmission in southern Malawi 21 May 2018

Spatially targeting malaria control interventions in areas of high disease burden will become a more cost-effective and sustainable approach for national programmes in the era of elimination. To achieve this the geographical scale in which to implement control and identify the most likely sources and routes of infection are critical. Wind-assisted mosquito dispersal is an important, yet currently undervalued, source of information to track the spread of malaria and predict outbreaks. We will develop and apply a model, previously and successfully used to track the wind-borne spread of Bluetongue virus by midges, to predict the spread of malaria in a rural region of southern Malawi. The ‘spatial-temporal wind-outbreak trajectory simulation’ (SWOTS) model will use wind data, household infection status and insect flight parameters to determine the most likely source and route of infection during the rainy season. We will empirically validate the output from SWOTS using a simple mark-recapture field experiment to determine the influence of wind direction and speed on vector movement. This pilot project will determine the applicability of SWOTS as a risk assessment and disease preparedness tool for malaria in rural Africa and lay the foundations to extend to other transmission settings and vector-borne disease systems.

Amount: £94,334
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine