- Total grants
- Total funders
- Total recipients
- Earliest award date
- 24 Jan 2017
- Latest award date
- 07 Dec 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.
Following a positive response to the preliminary submission for grant funding to establish a Dengue Controlled Human Infection Model (Dengue-CHIM ) in Ho Chi Minh City, Vietnam, I am submitting this request for a small grant to assist in refining and developing the main proposal prior to final submission in March 2018. During this pre-submission phase I plan to employ an experienced post-doctoral immunologist to carry out a) a scoping review of the current landscape of dengue vaccines in development, and b) a review exploring the current understanding of the immune response to/protection from DENV infection and disease, particularly focusing on immune correlates of protection. This will be the first application of a Dengue-CHIM approach in any dengue endemic setting, and raises a number of important bioethical concerns. Therefore I also plan to employ a Vietnamese social science research assistant for a period of 4 months to engage with key Vietnamese stakeholders to discuss the important issues surrounding endemic setting CHIMs, conduct preliminary informal interviews with these individuals, and help to develop the agenda for a 2 day workshop focused on Bioethics and Stakeholder Engagement related to endemic setting CHIMs that will take place in early March.
CpG islands(CGIs) are epigenetically specified elements that are intimately associated with over two-thirds of human gene promotors, yet whether CGIs regulate gene expression has remained enigmatic. This gap in our understanding of gene promoter function has serious implications for human health given that CGIs are perturbed in cancer and other debilitating human diseases. We have recently discovered that CGIs are recognized by reader proteins which can regulate gene expression. Capitalising on these advances, I will now discover how CGIs and the proteins that read them control the transcriptional machinery at gene promoters. I will achieve this transformative new mechanistic understanding through a multidisciplinary and hypothesis-driven programme of research that builds on a series of exciting new and unpublished observations to discover how CGIs function to activate(Aim1) and maintain(Aim2) transcription, and test whether CGIs create gene expression switches(Aim3). These new discoveries will help to redefine our understanding of how gene promoters function to control gene expression and will provide the basis on which new therapeutic interventions can be developed for diseases where normal CGI biology is perturbed.
Diarrhoea remains a major cause of childhood morbidity and mortality globally. The vast majority of the 2 billion annual diarrhoeal infections occur in low and middle-income countries (LMICs). Members of the genus Shigella are key agents of diarrhoea in LMICs, and S. sonnei is replacing S. flexneri as the predominant species globally. There is a necessity to improve our knowledge of S. sonnei infections in LMICs, with a specific requirement to better understand host-pathogen interactions and the natural history of disease in a setting where the organism is well understood, well described, and associated with a significant disease burden. Therefore, we aim to establish a Controlled Human Infection Model (CHIM) of S. sonnei diarrhoea in healthy Vietnamese adults. This is an innovative project will be the first CHIM study conducted at the Vietnam MOP. Therefore, it is imperative that the project is carefully designed in consultation with all relevant stakeholders. In order to ensure that the proposal is developed to the required standard in the timeframe available, I am requesting funds to employ an international postdoctoral assistant, with a background in microbiology and clinical research on a consultancy basis.
We wish to apply for funds to develop the malaria CHIM application. These are for a Co-investigators/stakeholders meeting to be held in Bangkok, Thailand, on 30th and 31st January 2018 and to support a writing meeting of the PIs in February 2018 in Kilifi, Kenya.
Neutrophils cause immunopathology by overproducing anti-microbial activities that may lead to tissue damage in inflammatory and autoimmune diseases, including rheumatoid arthritis, vasculitis, and lupus. Recent data highlight the existence of neutrophil subsets with different pathogenic properties. However the molecular control of pathogenic neutrophil responses is largely unknown. We will identify the intrinsic transcriptional circuitry that controls neutrophil functional reprogramming and provide insights into neutrophil heterogeneity and pathogenic phenotypes at sites of inflammation. Our recent studies highlighted a number of candidate transcription factors that will be functionally validated during the course of this project. Our work and the results of others have shown that neutrophil accumulation in tissues during sterile inflammation is controlled by macrophages. We will characterise how protein and lipid signals produced by monocytes and macrophages in the tissue at the different stages of inflammation affect neutrophil accumulation and activation and whether these are under a unified transcriptional control. Understanding the control of pathogenic neutrophil responses and identification of key regulators of immunopathogenic phenotypes will help to redefine these understudied cells in chronic inflammatory disorders and may lead to new treatments reducing the burden of human chronic inflammatory disease.
The human microbiota provides protection against pathogens via colonisation resistance. However, this resistance is not guaranteed, especially in the face of antibiotic treatment that suppresses the microbiota. My goal is to engineer communities for robustness to both antibiotics and pathogens. The challenge is that communities are complex systems containing many interacting and evolving species, making them challenging to predict and understand. Aim 1. Develop theory and analysis tools for complex microbial communities We will develop complex systems theory and quantitative tools to meet the challenges of understanding and engineering diverse communities. Aim 2. Apply theory to in-vitro gut communities We will apply our theory and test our ability to design gut communities that are robust to either antibiotic treatment, colonisation by the enteric pathogen Salmonella Typhimurium, or both. We will then study community and pathogen evolution: can a pathogen easily resist a probiotic community? Will the community evolve in response? Aim 3. Apply theory to S. Typhimurium pathogenesis We will study S. Typhimurium in gnotobiotic mice and test our ability to design robust communities in vivo. We will ask if S. Typhimurium can overcome in vivo colonisation resistance.
Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach 01 Oct 2017
Prof Rabbitts and colleagues from the Weatherall Institute of Molecular Biology have been awarded Seeding Drug Discovery funding to develop small molecules specifically targeting the RAS-effector protein-protein interactions. The RAS family of oncogenes is among the most frequently mutated in human cancers. Using minimal antibody fragments, the group has characterized an anti-RAS VH segment whose binding site covers the region of RAS where the signal transduction effector proteins bind, the “switch region.” In models of lung cancer this anti-RAS VH inhibits tumourigenesis, thus validating the mutant RAS-effector interaction as a therapeutic target. Using two different approaches small molecules have been identified that bind to RAS at the same point of contact as the anti-RAS VH. The Seeding Drug Discovery Award will be used to develop these hits through to leads and ultimately the identification of a preclinical development candidate.
My proposed research aims to understand the neural circuitry and neurochemistry of human decision making. Changes in the neurochemistry of prefrontal cortex can directly influence motivational and decision making behaviours. The circuit mechanisms by which this occurs remain unclear, but clarifying these mechanisms is important because it will help to bridge molecular and behavioural explanations of decision making. This will inform our understanding of several neuropsychiatric disorders that feature neurochemical (i.e. molecular-level) changes as part of their aetiology, and altered decision making behaviours as a cardinal symptom. My research has three main goals. First, I will develop novel neuroimaging-based measures of neural circuit computations within decision making tasks. Second, I will validate these measures via collaboration with researchers collecting non-human primate data. Third, I will use pharmacological interventions as a tool to understand the effects of neurochemical circuit manipulations in both species. This project aims to provide a holistic understanding of the neural circuitry and neurochemistry of decision making in the healthy brain. Ultimately, this work may provide the foundations required to index and understand neural circuit dysfunction in neuropsychiatric patients.
Combining genetics and high-resolution cell phenotyping to map pathways underlying inflammatory bowel disease 18 Oct 2017
Inflammatory bowel disease is a chronic, difficult to treat condition with unknown underlying causes. Given its high heritability, understanding IBD biology requires understanding how genetic risk variants impact the immune system. This project aims to identify measurable immune phenotypes through which IBD risk variants act, and investigate the impact of these phenotypes on disease prognosis. My first objective is to prioritize immune pathways where IBD genes are active, and develop methods of quantifying these pathways by phenotyping specific immune cells. I will use new statistical techniques to infer these pathways, single-cell analysis to discover impacted cell types, and collaborations with immunologists to establish phenotyping techniques. My second objective is to demonstrate associations between risk variants and candidate immune pathways. We will measure gene expression and readouts of immune function on IBD-associated cell types in 200 genotyped patients and 200 controls, and carry out eQTL, association and risk score analyses. My final objective is to build the groundwork for translating these discoveries into new treatments. We will test whether immune phenotypes predicted disease flares in our patients, and if so work with clinicians to design stratified medicine trials. We will work with partners to investigate future therapeutic interventions for these pathways.
Immunological mechanisms underlying the maintenance and function of human skin during homeostasis and inflammation remain poorly understood. The majority of our existing knowledge of human cutaneous T cell immunology is based on the study of peptide-specific T cell responses. However, recently it has become clear that T cell responses to lipid-based antigens make major contributions to normal physiology and inflammation in the skin. Specifically, the Major Histocompatibility Complex (MHC) class I-like molecule, CD1a, is highly expressed in human skin. Through collaborative studies, we have recently shown CD1a is able to present lipid antigens to skin T cells, contributing to the inflammatory skin response. The timing is therefore now ideal to address the underlying mechanisms in order to inform new approaches to treatment. In this multinational collaboration, with each principal investigator bringing complementary expertise, reagents and/or cohorts, we aim to investigate the role of lipids in human skin-based immunity. Our interdisciplinary approach will encompass lipidomics, chemistry, clinical dermatology, cellular immunology, and structural biology to identify and characterise the key parameters that define skin-based immunity to lipids. Such information will directly inform disease mechanisms and translational studies aimed at treating inflammatory skin diseases.
Centrosomes are the major microtubule organising centres in many animal cells. They form when centrioles assemble an electron dense matrix of pericentriolar material (PCM) around themselves. Several hundred proteins are concentrated in the PCM, including many cell-cycle regulators and cell signalling molecules, and centrosomes function as important coordination centres within the cell. The underlying principles that allow centrioles to recruit and organise the many proteins required to form a functional centrosome are largely mysterious. Recent studies from our laboratories have identified a surprisingly simple pathway of mitotic centrosome assembly that is conserved in flies and worms. The centriole and PCM protein Spd-2/SPD-2 recruits the mitotic kinase Polo/PLK1 and the large coiled-coil protein Cnn/SPD-5 around the mother centriole. Polo/Plk1 then phosphorylates Cnn/SPD-5, allowing it to assemble into a micron-scale structure that recruits other PCM proteins. Our studies suggest that Cnn/SPD-5 molecules phase-separate into a biomolecular condensate that functions as a "scaffold" that then recruits the many "clients" necessary for centrosome function. Our goal is to understand at the atomic level the nature of the interactions that drive the assembly of the mitotic centrosomal-scaffold, and, by comparting the two different model systems, to describe a conserved pathway for centrosome assembly.
Decoding the molecular identity of neurons 28 Nov 2017
Regulated gene expression underlies the specification of cell fate and the maintenance of cell-specific function. Cellular diversity is of particular importance in the brain where neural circuits are assembled from cells with unique properties. Many neurological and psychiatric conditions arise from dysfunction in the brain, and although molecules are the targets of therapeutic drugs, we know relatively little about those that are critical for specific neural functions. Here we propose to generate a single-cell resolution transcriptome of the entire fly brain using Drop-seq. In a unique collaborative effort we will mine this data set to uncover molecules that contribute to an array of important neural processes, including: 1. How does Kenyon cell diversity support memory-guided decisions? 2. What is the extent of input specificity to functionally discrete dopaminergic neurons? 3. How do particular peptidergic neurons respond to internal states? 4. How does sex-specific neuronal identity emerge? 5. Is there a rational transcription factor logic for cell-specific gene expression? Our endeavour also possesses significant technological value. Transcriptomic information, and the design of synthetic regulatory sequences that decode cell-specific patterns of gene expression, will improve the precision and resolution with which experimental effector genes can be targeted to pre-determined groups of neurons.
The idea that brief periods of coherence or phase-locking in rhythmic activity mechanistically facilitate communication across distributed cortical networks is hotly debated. It is thought to underlie processes like attention and working memory yet much of the evidence remains correlative. I propose to design and utilise a digital circuit to optogenetically entrain or damp rhythmic activity in one brain area based on oscillations occurring in other connected areas. Initially, I propose to use this circuit to determine if such processes drive dynamic connectivity across premotor and motor cortices facilitating the conversion of a motor plan to action. Specifically, I will perform closed-loop modulation of motor thalamo-cortical networks in behaving mice to determine if the projection from higher order motor thalamus to Layer 1 of cortex promotes such cortico-cortical synchronisation. Since higher order motor thalamus receives strong input from the dopamine modulated basal ganglia, I will also test if such subcortically mediated cortico-cortical synchronisation is important in driving cortico-cortical plasticity underlying motor learning. This will be accompanied with high channel count tetrode recordings distributed throughout the associated brain networks to capture changes in the spiking of individual neurons and LFPs, creating a rich data set to assess theories of oscillatory function.
Neural mechanisms supporting environment evaluation in humans and their breakdown in clinical disorders 08 Nov 2017
My goal in this proposal is to understand the neurocognitive mechanisms by which individuals evaluate their environment. First, I will use computational modelling to characterise how individuals adjust their estimates of the reward rate in an environment on a trial by trial basis. I will manipulate the reward rate over time and model how individuals respond to these changing dynamics. I will test models with 2 learning rates that allow estimates to be adjusted with different degrees of sensitivity (contingent on whether the environment is improving or deteriorating) against models that apply a single learning rate. I will then use fMRI to examine how the time varying components of computational models map onto brain activity during the task. Second, I will look to experimentally validate recent theoretical work from computational psychiatry which proposes that a pessimistic evaluation of an environments reward rate may underpin a number of the symptoms observed in clinical disorders. By using a threat manipulation, I will examine whether being in a temporary anxious state alters how individual update reward rate estimates. I will then examine whether this generalises to individuals with high levels of trait anxiety alongside other psychiatric disorders which share anxiety like features.
DNA sequences called enhancers control gene expression in time and space by activating genes during key cell-fate decisions. The specific combinations of genes activated by enhancers contribute to cellular behaviour, genetic predisposition to disease and phenotypic variation between species. My aim is to understand precisely how enhancers activate genes during differentiation. Investigating how globin genes are switched on during red blood cell (erythroid) differentiation has identified many general principles of mammalian gene regulation. It has recently been shown that activation of terminal erythroid genes depends on progenitors passing through a single, rapid S-phase. This previously undocumented link between differentiation and cell division provides a new, unexplored aspect of enhancer activity that may be of considerable general importance. To investigate enhancer function in terminal erythropoiesis, I will first analyse chromatin conformation, protein dynamics and single cell gene expression before and after this major cell state transition. I will then identify enhancer-binding transcription factors and co-factors required for terminal differentiation. I will study how they activate genes during this precise transition independent of their functions in other tissues or cell types. In addition to establishing how genes are regulated, this project will elucidate how enhancers are perturbed in human genetic disease.
The focus of this Fellowship proposal is on how vaccine platform affects the cellular drivers of humoral immunity, specifically memory B cells (mBCs) and T follicular helper (Tfh) cells. I will compare the leading Plasmodium falciparum blood-stage malaria candidate – RH5 – in two vaccine platforms: heterologous viral vectors (chimp adenovirus 63 prime, Modified Vaccinia Ankara boost) and protein with AS01 adjuvant. I have three main goals for this research. First, to compare the frequency and persistence of antigen-specific mBC and Tfh cells post-vaccination between vaccine platforms. Second, to identify the role vaccine platform plays in dictating Fc glycosylation profiles of anti-RH5 antibodies. Finally, to detect changes in protein expression in mBC and Tfh cells using RNAseq, indicating whether cellular pathways are differentially activated by vaccine platform. Taken together, these three sets of data will allow me to link mBC and Tfh responses to antibody quantity/quality, in the context of vaccine platform. Understanding how platform modulates mBC and Tfh responses will help us optimise vaccines to improve immunogenicity and protective efficacy. While my research will focus on blood-stage malaria, the conclusions should be translatable to other vaccine development programmes where antibodies are central to the mechanism of protection.
Overcoming contraceptive discontinuation by overcoming side-effects: paving the way for personalized contraception in Ethiopia 04 Dec 2017
In the developing world, millions of women discontinue hormonal contraception due to the experience of debilitating physiological side-effects (e.g. excessive and irregular bleeding), yet the causes of these adverse effects is not known. This project will be the first to test the hypothesis that side-effects are caused by unnecessarily high dosage of exogenous hormones in hormonal contraceptives (e.g. injectables) compared with women’s endogenous hormones, with the aims of accumulating primary evidence for optimizing contraception to communities and individuals. The research will focus on the use of injectables in Ethiopia, where unmet needs for contraception reach the highest levels in Africa. The PI will build on both an interdisciplinary team of researchers in anthropology, population health, epidemiology, microbiology and medicine and a long-term collaboration with the Institute of Development and Policy Research of Addis Ababa University to implement and run the project. The findings will act as a stepping stone to both engage pharmaceuticals and scale-up the research to produce a statistical model for delivering contraception, predicting, given a woman’s context, the range of contraceptive doses minimizing side-effects whilst still suppressing ovulation. This predictive model will be taken to stakeholders worldwide to stimulate transformational innovations for designing and delivering variable-dose contraceptives.
Timestamping Integrative Approach to Understand Secondary Envelopment of Human Cytomegalovirus 28 Nov 2017
The mechanisms facilitating the assembly of Human cytomegalovirus (HCMV) in the cytoplasm of infected cells, a complex process termed ‘secondary envelopment’, are poorly understood. Our goal is to identify in-situ the identity, position, and interactions of all the essential proteins involved in this critical stage of the viral ‘lifecycle’. Despite decades of research, it has been difficult to dissect the complexity of secondary envelopment, as bulk assays only show ensemble averages of populations of viral particles. To study these intermediates that are formed when cytoplasmic capsids acquire tegument proteins and their envelope membrane, we will develop a novel approach that separates these intermediates in time and space. We will provide their spatio-temporal models by integrating complementary cutting-edge techniques and expertise within this collaboration, including flow-virometry, correlative (fluorescence and electron cryo) microscopy, crosslinking and ion-mobility mass spectrometry-based proteomics, and computational modelling. Specifically, we aim to: -Identify key players in tegument assembly on capsids/membranes. -Elucidate the order and spatial organisation of tegument assembly. -Validate the interactions in vivo and analyse capsid tegumentation in vitro. -Integrate the information into a spatiotemporal model. This will significantly improve our understanding of herpesvirus assembly in general, a crucial step towards identifying new therapeutic targets.
The project will conduct a comprehensive review of community engagement using a realist review approach appropriate for tackling the conceptual complexity and practical diversity of the field. A review team with worldleading expertise in the theory and practice of CE will be supported by an advisory panel of internationally renowned realist review scholars. The review will begin with engagement with malaria research as a ‘pathfinder’ topic – and draw on a network of content experts, implementers and funders to input into and validate the review, ensuring its findings are widely disseminated and embedded in international CE work. Wellcome, BMFG and leading global health funders and implementation partners will benefit from a consolidated evidence base to underpin development of CE strategies in global health research and interventions. Outputs will include articles in peer reviewed open-access journals, an accessible evidence base on MESH/HELP, including context-relevant guidance for developing and evaluating CE strategies, and a critical mass of academics, practitioners, implementers and funders with a mutual interest in strengthening the theory and practice of engagement. In this way the review will spearhead the beginnings of a ‘science’ of community engagement and outline a clear value proposition for CE in global health research (14).