- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 06 Jul 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
This study will investigate the key ethical and regulatory considerations regarding human challenge studies (HCS) in endemic settings—and to examine the ethical processes (e.g., in the design, review, and conduct) involved in such studies to date (with a focus on recent HCS involving diarrheal disease in Thailand and malaria in Kenya and Tanzania). Our approach to this project will include two main data gathering processes: (1) review of relevant literature, and (2) qualitative research, involving in-depth interviews of those involved in the conduct and ethical review of recent HCS in endemic settings (focusing especially on HCS involving diarrheal disease in Thailand and malaria in Kenya and Tanzania) and other relevant stakeholders.
Neuroscientific and psychological studies have found that neural activity precedes the intention to act by several seconds, indicating that our actions are predetermined by unconscious neural computation. A major shortcoming of these studies is that the acts tested are trivial (e.g. move a finger at a time of your choosing), having no real-world implications. In a series of EEG experiments, we will assess complex choices that participants make. First, participants will be asked to choose to press one of two buttons. Then, they will be asked to a) ‘reward’ or ‘punish’ a person arbitrarily, b) reward or punish a person in response to a moral act, c) choose how much to reward or punish the individual based on their action, and finally, d) choose reward and punishment allocations within social or economic constraints, to reflect real-world decision-making. This will allow us to test if there is neural activity prior to the intention to act and also to compare between consequential and inconsequential choices. The investigation of neural activity in consequential action, examined in the light of philosophical analyses, addresses an essential unanswered question of past studies, and promises to shed new light on the nature and existence of free will.
The London Hub for Urban Health, Sustainability and Equity aims to be the world’s foremost transdisciplinary hub for research, training and pubic engagement on urban health. It is founded on two constituent projects – Complex Urban Systems for Sustainability and Health (CUSSH) and Pathways to Equitable Healthy Cities (PEHC) – and involves leading London-based institutions and their global network of collaborating institutions. The Hub’s principal objective is to integrate and coordinate research and stakeholder engagement that support evidence-based policies aimed at improving population health, health equity and environmental sustainability in cities around the world. The Hub, and its projects, will achieve this objective through comparative studies that involve participatory research and coproduction of knowledge among academic researchers, policy makers and practitioners, and civil society; developing models for prospective policy evaluation and applying these models to data from our partner cities; and training the next generation of research and policy leaders in urban health, while establishing the foundations for sustaining and expanding the Hub beyond the Wellcome funding period. The CUSSH project focuses on how to transform cities to address vital environmental and population health imperatives, and entails partnership with the cities of London, Beijing, Kisumu, Nairobi, Ningbo and Rennes.
An Extended Pilot for the Human Cell Atlas: Adult tissues, human development and inflammation-mediated pathologies 30 Sep 2018
The Human Cell Atlas (HCA) is an international, collaborative effort that "...aims to define all human cell types in terms of their distinctive patterns of gene expression, physiological states, developmental trajectories, and location". Here, we will contribute directly to the first phase of the HCA by forming an ‘extended pilot’ to implement UK infrastructure for large-scale, high quality human cell atlas experiments. We will generate a high-level atlas, with spatial resolution, for multiple adult human tissues along with matched data from human fetal material. We will then illustrate the power of a deep and focused investigation of a single tissue (skin) to produce highly-detailed data describing its cellular composition and spatial organisation. Finally, for selected tissues that have been profiled in adults and fetal material, we will analyse samples from immune-mediated disorders as a comparison with our reference data to gain deeper understanding of the pathological mechanisms. This will demonstrate the utility of the HCA as a ‘healthy reference’ for comparison with disease. Throughout, we will generate profound biological insight from primary human cells and lay a foundation of technology development and optimisation with a set of hardened and scalable methods for single-cell RNA-sequencing, spatially-resolved gene expression, and tissue imaging.
Toxic DNA: a model for all domains of life 17 Jul 2018
The instructions for life are encoded by DNA. As such, it is counter intuitive that certain DNA sequences can be intrinsically toxic to the cell. The problem is acute for DNA where the frequency of adenine and thymine exceeds what is normal for a given organism. Toxic effects of such AT-rich DNA have been reported for species as diverse as E. coli and humans. Working with bacteria, I have shown that misdirection of transcription is closely linked to the toxicity of AT-rich DNA. This happens because promoters, the DNA sequences that instigate transcription, are also AT-rich. Since promoters from all cell types have a high AT-content, I argue this may be a universal phenomenon. If true, the implications are far reaching; AT-rich DNA impacts processes as diverse as antibiotic resistance in bacteria and cancer in humans. My application probes the mechanistic details underlying the toxicity of AT-rich DNA for both prokaryotic and eukaryotic cell types. Hypothesis: The toxicity of AT-rich DNA is a consequence of spurious transcription Aim 1. Understand molecular basis Aim 2. Understand toxic mechanisms Aim 3. Understand evolutionary prevalence
Epilepsy is more common in Africa than other parts of the world due to high rates of head injuries and infection, which trigger inflammatory processes in the brain. How neuroinflammation causes epilepsy is not well understood. Disruptions in the transmembrane gradient for two key ions: chloride and hydrogen ions, are prototypic features of hyperexcitable neuronal networks. We hypothesize that neuroinflammation affects the cellular regulation of chloride and hydrogen ions, and hence seizure susceptibility in the brain. To test this hypothesis, we will utilize my expertise for measuring ionic changes in the brain together with rare access to human brain tissue donated by patients who have undergone neurosurgical procedures. Our first aim is to establish human brain slice cultures as a model system. We will then transfect different brain cell types with a genetically-encoded chloride and hydrogen ion sensor I have developed in order to generate the first baseline and activity-dependent measurements of these ions in living human neural tissue. Next we will determine how triggering an innate neuroinflammatory response in human brain slice cultures affects circuit excitability and seizure propensity. Finally, we will observe cell-type specific intracellular chloride and pH dynamics during the acute neuroinflammatory response in the human brain.
Nonsense mediated decay (NMD) is a quality control mechanism used by eukaryotic cells to destroy messenger RNAs containing incorrectly positioned translation termination codons . NMD, in combination with alternative RNA splicing (AS), also provides a potent mechanism for natural changes in gene expression in developing brain [2-5]. The main goal of my summer project will be to test the hypothesis that progressive down-regulation of an RNA-binding protein called PTBP1 during mammalian neurogenesis promotes neuronal identity by changing AS patterns and triggering NMD of multiple neural precursor-specific transcripts. I will first follow up on the RNA sequencing screen carried out in the Makeyev lab and validate bioinformatically predicted AS-NMD targets using Reverse Transcription PCR and quantitative PCR analyses of developing nervous system samples and embryonic stem cells undergoing neuronal differentiation in vitro. I will then analyse AS-MND regulation for one example showing the most robust regulation. This will be achieved by designing minigene and CRISPR-Cas constructs specific for AS-NMD promoting exons and testing these reagents in mouse ES cells undergoing neuronal differentiation or treated with siRNA against PTBP1. The results of this work should improve our understanding of the AS-NMD pathway and evaluate its contribution to neuronal differentiation.
The Effect of Acute Caffeine Ingestion on Cognitive Dual Task Performance During Assessment of Static and Dynamic Balance in Older Adults 31 May 2018
The ergogenic benefit of caffeine for sports performance has been reported extensively in younger adults (4) and recent evidence suggests benefits of acute caffeine ingestion for motor performance (5) and cognition (6) in older adults. Given such components are important mediators of postural control, it is proposed that caffeine may be an important nutritional supplement to improve balance in older adults. Studies examining the effect of caffeine on balance are sparse and focus only on static postural control (7). Such assessments give a limited understanding of balance tasks adopted during the completion of tasks of daily living, where falls are more likely during locomotory tasks requiring dynamic balance (8). Furthermore, individuals must maintain balance whilst completing secondary cognitive tasks such as communicating or crossing a road. Previous work had indicated that that completion of a secondary task can impair (9) or improve postural control but at the expense of the secondary task (10). It is unknown weather caffeine can mediate these detrimental effects. The present study aims to assess the effect of caffeine ingestion on cognitive dual performance during assessments of both static and dynamic balance in older adults.
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.
Neurotrophins and their receptors play a key role in the maintenance and remodelling of the nervous system, and defects in trophic signalling are associated with mental illness as well as neurodegeneration. To date, the cellular mechanisms regulating neurotrophin receptor bioavailability are not fully understood. Here we focus on BDNF and its receptor, TrkB, which are widely expressed throughout the central nervous system. This project will investigate the role of two novel potential TrkB regulators that recently emerged from our screens. Candidates will be expressed in HEK-TrkB cells and primary cortical mouse neurons, and (i) TrkB receptor expression levels and (ii) downstream signalling events will be investigated using both Western blotting and immunofluorescence techniques. These experiments will address whether the candidates modulate TrkB availability and activity. A better understanding of the cellular mechanisms underlying TrkB regulation may highlight potential therapeutic targets to counteract TrkB degradation and restore sensitivity of vulnerable cells to the beneficial actions of BDNF.
The aim of this project is to investigate whether specific metabolites produced in the duodenum during digestion and correlated with the release of the gastrointestinal hormone glucagon-like peptide-1 (GLP-1) actually drive this release of GLP-1 to regulate energy and glucose homeostasis. We will use gut organoids as a model of enteroendocrine cell function to study the effects of the metabolites tyrosine, taurine and acetone, alone and in combination, and with or without glucose present. Hypothesis: Tyrosine, taurine and acetone will stimulate GLP-1 release from duodenal organoids Aim: To investigate the effects of tyrosine, taurine and acetone on GLP-1 release Objective: To establish whether tyrosine, taurine and acetone alone or in combination with each other or glucose stimulate GLP-1 release from duodenal organoids This work will establish the possible role of these metabolites in driving GLP-1 release, and thus whether using them as dietary supplements may represent a potential therapeutic approach to obesity and metabolic disease.
Seizures in absence epilepsy are characterised by brief lapses in consciousness and cessation of ongoing behaviour. They occur concurrently with aberrant rhythmic electrical activity across the whole brain in the form of oscillations named Spike and Wave Discharges (SWDs). It is widely agreed that SWDs are generated in the cortico-thalamo-cortical (CTC) circuit that consists of neurons that run within and between the cortex and the thalamus. The activity of neurons in many components of the CTC circuit are already well characterised, apart from that of the intralaminar nuclei of the thalamus (ILNs), a group of neurons that respond in an abnormal, yet consistent way during seizures. The electrical activity of single neurons in the ILNs will be recorded and manipulated in order to physiologically characterise them and understand how changing their firing pattern can alter SWDs. The techniques required to achieve this are too invasive to be completed in humans, therefore, these methods will be undertaken in genetic and pharmacological rodent models of absence epilepsy. This work will provide a better understanding of the role of ILNs in the generation and spread of SWDs and in CTC circuit function, potentially leading to novel therapeutic approaches in absence epilepsy.
To help facilitate progress on a path to implementation and global coordination of promising market entry rewards, such as the PAVE Award, or other incentive models, Duke-Margolis proposes to advance the conversations and develop implementation approaches. This project has three primary goals: 1) to develop and refine technical details for incentive models, such as the PAVE Award, needed for implementation in the United States (US) market, 2) to identify broader options to support the sustainability of such reward models, and 3) to support development of principles and approaches for global coordination.
Cellular Dynamics and Regulatory Networks Controlling Endometrial Remodelling during the Window of Implantation 17 Jul 2018
The endometrium undergoes iterative cycles of menstrual shedding, regeneration, rapid growth, and differentiation in response to ovarian hormones. During the mid-luteal phase, the endometrium becomes transiently receptive to implantation, heralding the start of a process of intense tissue remodelling, characterized by secretory transformation of glandular epithelium, angiogenesis, differentiation of stromal cells into secretory decidual cells, and activation of specialized immune cells. Several reproductive disorders, including recurrent pregnancy loss, are linked to defects in tissue remodelling at implantation. However, the cellular complexity and dynamic nature of the endometrium have so far precluded precise characterization of the underlying pathological mechanisms and drivers. We will employ high-throughput single-nucleus sequencing to map the dynamic changes in gene expression and chromatin accessibility (cis-regulatory regions) in all endometrial cell types across the luteal phase in defined patient groups. The data will be back-mapped to a future successful pregnancy or miscarriage. This analysis will yield unparalleled insight into the sequence of endometrial events (i.e. changes in cell populations, cellular states, gene expression and transcriptional regulation) leading to a successful or failed pregnancy. Further, 3D organoid cultures, consisting of glands and stroma, will be used to investigate putative drivers of endometrial dysfunction and to evaluate new treatment targets.
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.
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.
Modelling the feasibility of achieving 70% target vaccination coverages for rabies elimination in free-ranging dog populations in India 30 Sep 2018
Rabies kills over 20000 people every year, predominantly in India, where it is spread by the bite of infected free-ranging dogs. The WHO recommends that canine rabies can be controlled and eventually eliminated by consistently vaccinating at least 70% of the dog population in a region. However, there is little information on dog populations in India and what proportion are truly free-ranging. This influences the feasibility of conducting mass rabies vaccination campaigns and achieving the target of 70% vaccination coverage. This study will look at dog populations at selected sites in India to estimate population size and structure such as proportion of males and females, young and adult animals and the occurrence of rabies. The study will assess ownership patterns to determine what proportion of dogs are truly free-ranging. Rabies vaccination campaigns will be conducted at these study sites to determine the feasibility of achieving 70% vaccination coverage. The data on dog population and vaccination coverage will be used to mathematically model the effects of this kind of intervention, and determine the best way to implement it at these sites. The results of this study will directly inform rabies prevention and control strategies at the regional levels and in India.
Investigating non-canonical programmed ribosomal frameshifting in porcine reproductive and respiratory syndrome virus 30 Sep 2018
RNA viruses are under selection pressure to maintain a small genome, however they still need to produce a variety of proteins. To overcome these conflicting pressures, many viruses use non-canonical methods of translation control. One example of this is programmed ribosomal frameshifting (PRF), in which a percentage of ribosomes, while translating a ‘slippery sequence’ slip one or two nucleotides out of frame, consequently translating the remainder of the mRNA in a different reading frame and allowing expression of more than one protein from a single gene. This is normally stimulated by a downstream secondary RNA structure, however there are two known examples of a trans-acting viral protein being used as the stimulatory element. One example is found in the genome of porcine reproductive and respiratory syndrome virus (PRRSV): an Arterivirus that infects pigs, causing an estimated annual cost to the US swine industry of $664m. I will use structural techniques such as X-ray crystallography to derive information about the RNA/protein complex, and will investigate the efficiency and mechanism of this non-canonical PRF using ribosomal profiling in parallel with RNASeq. The latter will also allow me to analyse host and viral gene expression, to examine host-virus interactions in this important pathogen.