- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
The regulation of gene expression is fundamental for cellular integrity and is partly achieved by the opposing action of repressive and activating histone modifications. One such histone modification is the tri-methylation of lysine 4 on histone H3 (H3K4me3), which is known to correlate with transcriptional activity. The SET1A complex is responsible for depositing the majority of H3K4me3 in mammalian cells and disrupting its function often leads to gene expression defects. However, the mechanisms by which SET1A regulates gene expression remain unknown. I will use the auxin-inducible degron system to rapidly deplete SET1A levels. A series of genomics technologies, including ChIP-seq and NET-seq will then be used to determine the effects of SET1A loss on chromatin architecture and transcriptional activity. Additionally, proteomics techniques will be used to identify the pathways perturbed upon SET1A loss, hence identifying the mechanisms by which SET1A supports active transcription and furthering our understanding of how gene transcription is regulated. This is essential for the development of novel therapies targeting genetic diseases in which the control of gene expression is perturbed.
Spinal cord injury is a devastating condition that may lead to loss of limb movement, sensation and bladder control. Despite intense research, treatment is still very limited. Most research to date has focused on biochemical signalling. However, some more recent studies have hinted that mechanics might play an important role in spinal cord regeneration. Using atomic force microscopy (AFM), a cutting-edge technique which allows us to very precisely measure stiffness maps of biological tissues, we will investigate the stiffness of spinal cord tissue at various time points after injury and compare this to the stiffness of healthy spinal cord. We will test whether artificially modifying the stiffness of the damaged spinal cord or modifying mechanosensing in spinal cord cells improves regeneration of neurons after spinal cord injury. Our studies will be carried out in a cervical contusion model in rats which closely mimics the pathology seen in the human spinal cord after injury, even though the behavioural impairments the animals show are markedly less grave.
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.
Structural studies of the host-parasite interactions at the heart of malaria pathogenicity 05 Apr 2018
Our proposed activities consist of two major strands. Firstly we wish to take our research on tour, developing a high quality interactive stall which will allow us to present our findings to those who visit science fairs. We have secured a place at the Royal Society Summer Science Exhibition in July 2018, as the first outing for our display and this provides the deadline by which we must have the stall in place. As this is one of the UK’s premier science festival, visited by ~13,000 people each year, this is a great opportunity to meet people and to share our research. We will also ensure that our stand is fully updateable in content – for example using interactive screens which can be altered over time. We will next present at the Oxford Science Festival in 2019 and 2020, at which the Biochemistry Department has committed space. We will also apply to present at another major science festival as soon as applications open (i.e. Cheltenham and Edinburgh) in each of 2019 and 2020. This will be supported by digital content, including a ~2 minute video which will describe our approach towards rational malaria vaccine design and will be posted on Youtube. We will also develop an interactive vaccine game in which players can allocate health budgets and see the effect on malaria prevalence. Together with informative content about our research, these will widen the accessibility of our research.
Membrane proteins account for ca. 20% of all genes, 40% of drug targets, and are mutated in many human diseases. The past decade has witnessed an exponential rise in the number of high resolution membrane protein structures. Interactions with lipids are of crucial importance for the stability, regulation, and targeting of membrane proteins, but structural and biophysical data on membrane protein-lipid interactions remain sparse. Molecular dynamics (MD) simulations provide a key tool for probing the interactions of lipids with membrane proteins. The overall aim is to apply multiscale simulations to predict specific lipid interactions of lipids with recently determined cryoEM structures of selected membrane proteins. This will be achieved by a serial multiscale approach. Coarse-grained simulations will be used to identify the interaction of membrane proteins with the lipids of complex membranes (i.e. in physiologically relevant mixed lipid bilayers based on lipidomics data). Atomistic simulations will be used to refine the resultant models. Predictions of protein/lipid interactions will be tested experimentally via our collaborators.
What Are The Roles Of MEIS1, BMI1 And HOXB Genes In Self-Renewal Of Acute Myeloid Leukaemia Stem Cells? 30 Sep 2018
Acute myeloid leukaemia (AML) is the commonest aggressive leukaemia in adults. Due to treatment resistance and relapse, the prognosis for most patients is poor. In normal blood cell development, stem cells are the most immature cells and can produce any type of blood cell. AML results when bone marrow cells acquire genetic alterations, called mutations. These mutations occur in early bone marrow cells and result in a ‘leukaemic stem cell’, which maintains growth of the leukaemia. Previous work in the Vyas laboratory has identified genes that are switched on in AML patients that cause leukemic stem cells to grow abnormally, including HOX genes. This project aims to further our understanding of the impact of these genes in leukaemic stem cells by answering questions such as: Is AML cell growth impaired when these genes are switched off? Do leukaemia cells behave like normal blood cells when these genes are switched off? Does switching on the genes make normal bone marrow cells behave like leukaemia cells? What mechanisms allow these genes to regulate the function of leukaemia cells? Our overall aim is to use this information to design treatment strategies to eradicate leukaemic stem cells.
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.
Biomedical sciences increasingly recognise the importance of mechanobiology in health and disease. While most mechanisms of the immune response are adequately explained by cell-biology, biochemistry, and genetics, many of its features profoundly depend on biomechanical aspects. One such scenario involves the ability of immune cells to differently respond to antigens with similar binding affinities, highlighting additional parameters needed to fully explain antigen discrimination. Emerging evidence indicates that immune cells dynamically adjust their biomechanics to facilitate this process. The principle goal of this project is to uncover how biomechanical feedback modifies the mechanobiology of activating T-lymphocytes by altering the dynamic assembly and organisation of actin structures, hence adjusting the sensitivity of antigen recognition. With the advent of immune checkpoint blockade and T-cell re-direction there has never been more interest in controlling lymphocyte responses, and biomechanical signal integration has received relatively little attention despite the consistent failure of biochemical parameters to account for T-cell discrimination of different antigens. To address this research project, I will lead a team to apply new state-of-the-art force probing technology coupled with high-speed super-resolution microscopies, overcoming the limitations of previous approaches to generate a breakthrough understanding of mechanobiology in immune cell activation.
The Effect of Priorizing Information in Working Memory on Later Behavioural Interference 31 May 2018
This experiment will investigate how prioritised information is represented in working memory (WM) through looking at the serial dependence effect. Myers and colleagues (2017) have suggested that items which are prioritised in WM are transformed into action-ready representations. Therefore, the theory predicts that the difference between prioritised and non-prioritised representations in WM will be reflected in behavioural findings. The serial dependence effect occurs when visual information from the recent past biases perception and behaviour at the present moment (Fischer & Whitney, 2014). If prioritised WM items were stored in an action-oriented format, we predict it will show these interference effects in behaviour more than non-prioritised information. By using an orientation adjustment paradigm, we will measure the serial dependence effect for prioritised WM items (which have been retro-cued) versus non-prioritised WM items. In addition, we will vary the type of testing (forced choice versus free recall), predicting that more interference will occur when the tests are the same than when different, due to the action-based nature of the WM representation. Initially we will use behavioural measures (reaction times) to measure the interference effects, extending to EEG to measure neural evidence for the carry-over effects.
The Role of Cyclophilins in Innate Immunity 30 Sep 2018
The Cyclophilins are a widely expressed, broad acting family of proteins defined by their common enzymatic domain. Among their multiple roles, they are reported to be involved in viral infections (including HIV, Hepatitis, and Influenza infections) both to the benefit and the detriment of the host. Despite this, much is still unknown about whether they play a role in the innate immune system. In the past this research has been limited due to the broad reactivity of the innate immune cells. However, with recent progress in stem cell research and CRISPR gene editing technology, we are now capable of manipulating these cells far more effectively. Therefore I intend to use these advances to knock out each member of the Cyclophilin family and then challenge my cells with a range of immune stimulants looking for changes in innate cell activation and protein secretion. Combining my panel with a pharmacological approach targeting virus-cyclophilin interactions, I also intent to determine whether HIV-1 uses only Cyclophilin-A during infection and discover novel Cyclophilin interacting proteins. These studies aim to lead to a better understanding of the fundamental functioning of cells in response to various threats, and may lead to pathogen specific drug therapies targeting Cyclophilins.
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.
Identifying suppressor mutations of ATR-X and ADNP syndromes using a novel CRISPR-based screening method in mice 24 Apr 2018
The recent Deciphering Developmental Disorders Study found that mutations in genes encoding epigenetics proteins are a primary cause of intellectual disability. These disorders are incurable and their underlying mechanisms remain elusive. Intriguingly, varying symptom severity has been described in patients with the same causative mutations for a number of these disorders and phenotypes displayed in some mouse models are strain-dependent. To search for secondary mutations that suppress phenotypes in mouse models of the neurological disorder, Rett syndrome, Monica Justice’s lab performed a genome-wide screen by inducing random mutations with the chemical mutagen ENU. I aim to take advantage of recent advances in CRISPR/Cas9 technology to develop a CRISPR-based screening method. This method will simplify isolation of modifying mutations, greatly reduce the number of animals required and can be adapted for recessive screening. I will use this method to screen for suppressors of two neurological disorders that are predicted to be modifiable: ATR-X and ADNP syndromes. Both causative genes encode epigenetic proteins: ATRX is a chromatin remodelling ATPase and ADNP is a putative transcription factor. I hope that the ‘hits’ obtained in these screens will help us to better understand ATRX/ADNP protein function and open up therapeutic avenues for patients.
Globally, medicine regulatory authorities, research groups, international organisations, law enforcement agencies and other key stakeholders, including the pharmaceutical industry, are trying to keep patients safe and ensure that the benefits of modern medicine are delivered to patients. However, organisations working in this field tend to be fragmented with the wide diversity of professionals required to tackle this important issue, from chemists to lawyers, rarely discussing solutions together. Indeed, there has never been an opportunity for the diverse stakeholders involved in medicine quality and drug regulation to come together – within the framework of a specific academic conference – to share ideas and expertise, and to outline the coordinated steps that need to be taken to tackle the problem on an international scale. Drawing on the achievements of our successful, annual, multidisciplinary course on the Quality of Medical Products & Public Health at the London School of Hygiene & Tropical Medicine and Boston University, we are organising the first-ever dedicated academic and programmatic conference on Medicine Quality and Public Health. Wellcome is supporting the attendance of 10 participants from LMICs.
Public Engagement Provision. 20 Apr 2015
It is anticipated that by 2020 there could be considerable advances in genomic medicine. However, even with demonstrated clinical utility it is uncertain whether such advances will have benefits for patients, because research findings are not routinely implemented into clinical care. To facilitate translational research new sets of partnerships and ways of working are needed between patients, clinicians, researchers and commercial partners. Biobanks potentially lie at the heart of these new rela tionships, as they can be used for patient care, but also for different kinds of research. For biobanks to become key nodes in translational research new practices, policies and protocols are needed. This research will carry out a number of interviews and workshops with stakeholders involved in the Oxford Radcliffe Biobank (ORB) to understand the issues at stake. I will also draw on best practice elsewhere in the world, particularly the US and the Netherlands, to help develop practical solutions in this rapidly changing field. This research will provide an evidence base for national policy formulation which could make ORB an exemplar of best practice for clinical biobanks in the UK. Lessons learnt within ORB could be applied elsewhere in the UK and Europe where similar initiatives are underway.
In 1971, Chefaro, a subsidiary of the Dutch firm Organon, launched Predictor, Britain's first HPT. This project will recover the history of HPTs from c.1970 to the present day, when their widespread visibility and availability is taken for granted. It will be divided into four parts. Part One examines how Predictor, a laboratory tool repackaged, but not redesigned, for domestic use, was produced and marketed, received by consumer watchdog organisations, and appropriated by women's liberation gro ups. Part Two examines the public debate over Schering's Primodos, a controversial pregnancy test drug that was taken off the market in 1978 amidst fears of a repeat of the Thalidomide tragedy. Part Three investigates how not only technological innovation and slick marketing, but also NHS cutbacks and the rise of IVF contributed to the runaway commercial success of Clearblue, launched by Unipath, a subsidiary of the multinational Unilever, in 1985-88. Part Four recovers the mainstreaming and aes theticization of pregnancy testing in fiction, cinema, television, comics, artworks, and new media to reexamine assumptions about the textual and visual politics of reproduction, currently strongly identified with highly charged images of the late-term human fetus and 'baby bump'.