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Recipients:
University of Cambridge
Award Year:
2018

Results

Understanding Medical Black Boxes: A Philosophical Analysis of AI Explainability 26 Jul 2018

I plan during the next two years to develop a major, multi-year project into AI explainability in medical contexts. This project will connect existing literatures in philosophy of science, philosophy of medicine and medical ethics, where problems of understanding and explanation have been extensively studied, to the emerging literature on explainability in machine learning and the ethics of AI. The aim will be (i) to enhance our understanding of the problems AI systems raise for explainability in medical contexts and (ii) to collaborate with machine learning researchers to develop technical research apt to address these problems. The existing literatures on explainability and understanding in medicine are vast and have not previously been systematically connected to the ethics of AI. To lay the groundworks for a later grant proposal, this application proposes to conduct three pilot-studies, focusing on potential challenges from AI to: (1) mechanistic understanding, (2) clinical judgement and diagnostic reasoning and (3) informed consent. A part-time research assistant will assist in scoping the relevant literatures. Travel to groups at other universities and a workshop in Cambridge will furthermore help establish contacts with a network of researchers interested in the ethics of AI and AI explainability in medical contexts.

Amount: £86,561
Funder: The Wellcome Trust
Recipient: University of Cambridge

Menstruation and the moon in early modern England 08 May 2018

The association of menstrual synchrony with the moon relates back to ancient mythologies. Historians largely dismiss the relevance of a lunar theory of menstruation by the Middle Ages, but the moon’s ability to disturb a woman’s womb through her menstrual blood was continuously discussed by early modern medical and natural philosophical writers. This project asks how the sympathetic connection between menstruation and the moon was manifest in learned discourses, vernacular knowledge, and everyday practices. Answering this requires studying women’s knowledge, the relationship between natural and occult philosophy, and the link between theory and practice in medicine. This research draws together rich, diverse manuscript and printed sources to demonstrate how the influence of the moon over the female body was ubiquitous in early modern medicine and natural philosophy. In vernacular medical handbooks, the moon was a popular socio-cultural symbol of femininity and sexual difference. Its power over the female body was demonstrated through practice in recipe books, casebooks, female-authored almanacs and medical treatises on phlebotomy. The cause and consequences of its influence were debated through learned discourse, highlighting the temporal dynamics of menstruation, and the continuous significance of fluids to changing intellectual frameworks of the body.

Amount: £100,057
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Epigenetic control of neurodevelopmental gene regulatory networks linked to neurodegeneration 30 Sep 2018

Dementia is predicted to affect 130 million people worldwide by 2050 according to the World Alzheimer 2015 Report30. Some familial forms of dementia inherited in autosomal-dominant fashion are linked to mutations altering gene dosage2,8,14,16,19,23,25. Patients with the mutations display a long pre-symptomatic phase during which cellular changes may take place before the onset of the disease decades later23. The cellular changes are reflected in gene regulatory networks3,4,5,12,28,31. As evidence from other neurodevelopmental conditions suggests10,13,17, changes during early neural development may lead to onset of the disease decades later. In order to study the neurodevelopmental gene regulatory networks and their links to dementia, I would like to focus on two forms of their regulation: small RNAs and demethylation escapees. Demethylation escapees are regions of the genome that escape epigenome resetting during early embryonic development27. Small RNAs have an important role in neural development and gene regulatory networks controlling them1,6,20,24. In order to address the question, I will use RNA and whole genome bisulfite sequencing methods of neurons derived from human stem-cells from familial dementia patients, combined with bioinformatics analyses. Focusing on small RNAs and demethylation escapees, the project might hint at neurodevelopmental gene regulatory pathways dysregulated in autosomal familial dementia.

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

Regulation of Neural Stem Cells 30 Sep 2018

Of all the tissues and organs in the human body the nervous system is the most intricate and complex, consisting of more than 100 billion neurons. These neurons make precise connections with each other to form functional networks that can transmit information at amazing speed over considerable distances. Neurons are produced by neural stem cells, which renew themselves at each cell division while also giving rise to all of the diverse types of neurons in the brain. The Brand lab is interested in how the environment influences stem cell behaviour, in particular how nutrition regulates neural stem cell proliferation. Uncovering the molecular mechanisms that control whether a stem cell chooses to proliferate or remain dormant is crucial for understanding tissue regeneration under normal and pathological conditions and in response to ageing. It is critical to learn not only how stem cell proliferation is induced but also how stem cells can return to a dormant (‘quiescent’) state, as uncontrolled stem cell division can lead to cancer, including brain tumours like glioma. A thorough appreciation of the signals, both extrinsic and intrinsic, that control stem cell behaviour is necessary to understand how homeostasis is achieved and maintained in the brain.

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

Analysis of Inflammatory markers in chronic subdural haematoma 31 May 2018

This project plans to measure levels of tissue plasminogen activator (tPA) which is involved in fibrinolysis of blood clots within the CSDH lesions. This bleeding is an essential part of CSDH formation, followed by coagulation and fibrinolysis which is triggered by the cleavage of plasminogen by tPA to generate plasmin. tPA will be measured in these samples using the commercially available ELISA kit. I will determine whether levels of tPA are correlated with levels of other inflammatory markers in CSDH fluid or in blood, and also to examine if increased tPA levels at the site of the haematoma predicts risk of CSDH recurrence. If tPA concentrations in blood or CSDH fluid correlate with clinical outcome, this could be used clinically to decide whether surgical or pharmacological management are most appropriate for individual patients. Finally, the effects of dexamethasone treatment on levels of tPA and other cytokines will also be determined, by comparison of dexamthasone and placebo-treated patients. These patient samples are anonymised and will only be unblinded after measurement of the above analytes has been completed.

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

The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge 30 Sep 2018

Since 2013, the University of Cambridge Metabolic Research Laboratories (MRL) has developed into a world-leading centre for basic and applied research in obesity and related metabolic disease. Underpinning funding from Wellcome, which has provided new clinical research facilities and other crucial core support, has been central to this success. Importantly, this endeavour has been undertaken in partnership with the MRC, who have funded a new Unit, the Metabolic Diseases Unit (MDU), which is embedded in the MRL. The MRL, together with the MRC Epidemiology Unit (Dir. Wareham) and cognate clinical facilities, form the Wellcome Trust-MRC Institute of Metabolic Science (IMS) which operates seamlessly from basic science through to population science, translational research and delivery of ambulatory care within a single co-ordinated institute. The current bid is focused on further developing world-class metabolic research within the MRL through core support for clinical and animal model research as well as underpinning laboratory science at an internationally leading level. Given the centrality of bioinformatics to all contemporary biomedical research, we have placed a particular emphasis on development of this area for the next phase of our evolution.

Amount: £4,795,450
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the role of mechanical forces in cell exit from the Zebrafish tailbud 30 Sep 2018

During the elongation of the embryonic body, groups of stem cells within the tip of the embryo continually generate progenitor cells that later make up the spinal cord and segmented vertebrae. Interestingly, differentiation of other embryonic cell types has been shown to be influenced by mechanical forces from the environment surrounding the cells in culture. Over the course of my PhD I will investigate the influence of the native mechanical environment on the differentiation of progenitor cells in the zebrafish embryo into cell types contributing to the formation of specialised tissues. This will aid in our understanding of how mechanical properties of tissues, such as their stiffness, can influence cell differentiation. Firstly, I will characterise cell movement, cell shape, and environmental stiffness coinciding with cell state transitions in the tailbud. Secondly, I will investigate the influence of mechanical forces on differentiation and epithelial to mesenchymal transitions. Finally, I will investigate the role of YAP in regulating differentiation into spinal cord and mesodermal cell types. These studies will provide important insight into the fundamental problem of how cell fate decisions and cell movements are coupled during embryonic development.

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

Mechanisms of lineage commitment during exit from pluripotency in vivo 30 Sep 2018

In early mammalian development, a pool of cells in the embryo can generate all cell types of the body, an ability referred to as 'pluripotency'. Specification of the cells is regulated by selective activation of genes that define tissue identities. These developmental programs are regulated by proteins known as 'transcription factors' that direct expression of other genes. However, the precise mechanisms that control cell fate specification are still poorly understood. The aim of my project is to understand the molecular mechanism of how genetically identical cells can be instructed to differentiate. I will focus on understanding the functional role of covalent 'epigenetic' DNA modifications in cell lineage priming and specification. To be able to address this fundamental question, I will use mouse embryos and stem cell culture systems, linked to imaging and single cell technologies to study the effect of perturbation of DNA modifications on cell fate specification. The results from my project will help us to understand how cells regulate their fate in early development. This is of great importance to understand developmental defects and learn how to instruct stem cells in culture for differentiation for potential use in cellular therapies in regenerative medicine.

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

Investigating the effect of the Drosophila mitochondrial genome on complex phenotypes 30 Sep 2018

The mitochondrion, known as the powerhouse of the cell, contains its own genome (mtDNA). The multi-copy mtDNA works with the nuclear genome to control energy production and various cellular activities. To date, mtDNA mutations are among the most common genetically inherited diseases and the mitochondrial replacement therapy has been approved in the UK to make three-parent babies. However, our knowledge of mtDNA biology and how it can affect organismal traits is rather limited. This is largely due to a lack of powerful genetic tools to study mtDNA. A recent study in Ma's group shows that Drosophila mtDNA can undergo homologous recombination12. Further, they established a system to induce recombination at specific sites and select for different recombinant genomes. This work not only provides a definitive resolution to the existence of recombination in animal mitochondria, but opens up the possibility of developing a recombination system for functional mapping and manipulating animal mtDNA. In this project, I will isolate recombinant mitochondrial genomes to map/define mtDNA variations responsible for longevity and fertility to accelerate our understanding of how mtDNA impacts health. Meanwhile, I will identify key components of the recombination machinery to better understand how mtDNA is maintained during aging and evolution.

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

Mycobacterial Determinants of Extracellular Success 30 Sep 2018

Tuberculosis (TB) is a severe infection which affects over ten million people a year, causing 1.7 million deaths annually. Treatment takes at least six months and four different drugs, and resistance to these drugs is an increasing problem. The causative bacteria, Mycobacterium tuberculosis (Mtb), lives mainly inside human cells. However, it must ultimately escape those cells to spread to the next host, a stage associated with worsening clinical disease. Despite its importance, little is known about how Mtb survives and thrives in this extracellular stage. This research will focus on understanding how the bacteria escape immune cell uptake, and whether they are using specific tactics such as 'biofilm' formation and 'quorum sensing'. Biofilm formation and quorum sensing are forms of bacterial behaviour that allow individual bacteria to ‘talk’ to each other via chemical signals, and set up collaborative, hardy, multifunctional colonies that can resist stresses including the immune response and antibiotics. In many other chronic human infections, biofilms are commonly seen and make the disease very hard to treat. This research will seek information about the genetics, regulation, and impact of biofilm formation in TB in order to unlock new knowledge about drug treatment and onward transmission of disease.

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

Disorders of Thyroid Hormone Action: Diagnosis, Pathophysiology and Therapy 10 Apr 2018

Having discovered that cystic degeneration of aortic media in human selenoprotein deficiency causes its aneurysmal dilatation, we will elucidate its pathogenesis using mice with conditional, aortic selenoprotein depletion and patients stem cell-derived vascular smooth muscle cells and determine whether antioxidants can inhibit this process. We will investigate structure-function relationships in SECISBP2, including how deficiency of this master regulator is variably rate-limiting for synthesis of different selenoproteins. Following our first identification of RTHalpha, a disorder due to TRalpha mutations with tissue-selective hypothyroidism but near-normal thyroid hormone levels, we will determine its genetic architecture and phenotypic spectrum. We will identify abnormalities in circulating metabolites and proteins to enable diagnosis of RTHalpha and guide its therapy. Aided by structural insights, we will design and test thyroid hormone analogues that disrupt mutant TRalpha-corepressor interaction, the basis of dominant negative inhibition which mediates pathogenesis of the disorder. We will develop biochemical markers to differentially diagnose RTHbeta cases from patients with TSH-secreting tumours and to guide RTHbeta therapy. In patients with deficiency of the MCT8 thyroid hormone transporter, we will trial whether treatment with triiodothyroacetic acid, a thyroid hormone analogue whose cellular transport is MCT8-independent, alters neurodevelopmental outcome.

Amount: £1,601,565
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of the Wallerian axon-death pathway in neuronal and axonal vulnerability in Parkinson's disease 24 Apr 2018

Parkinson’s disease (PD) involves preferential loss of substantia nigra pars compacta (SNc) dopaminergic neurons and their projecting axons to the striatum. SNc neurons have huge, highly branched and vulnerable axons, whose distal ends are lost first in PD, so preventing this will be essential for any disease modifying therapy. Our preliminary data suggest the involvement of an axon-death pathway in PD shared with the loss of injured axons (Wallerian degeneration). The Wallerian pathway is initiated by loss of the activity of the essential NAD-biosynthetic enzyme NMNAT2 in axons. Crucially, axons expressing lower levels of NMNAT2 are more vulnerable, raising the possibility that SNc neuron and axon susceptibility in PD reflects a particular sensitivity to Wallerian pathway activation. To test this hypothesis, I will use cutting-edge research strategies from three leading laboratories in axon degeneration and Parkinson’s disease, combining expertise in mouse primary neuronal cultures, human iPSC-derived dopaminergic neurons and mouse and zebrafish in vivo models of PD. The proposed research will greatly advance our understanding of mechanisms of SNc neuron and axon death in PD. In the longer term, this work has significant clinical implications since axons are lost early in PD and the Wallerian pathway can be potently blocked.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

The neural dynamics of how expectation modulates visual object recognition 06 Jun 2018

How do we understand what we see? Recognising objects depends on dynamic transformations of information from vision to semantics - but in the real world, our understanding of what we see is shaped by the environment. When we see an object, we are already in a complex and rich environment, which leads to expectations about the kind of things we may see. The over-arching vision for this fellowship is to understand how the environment shapes the neural dynamics and mechanisms of object recognition, most saliently in terms of the fundamental components of recognition - visual and semantic processing. This research will test how environmental context changes neural dynamics prior to seeing objects, and how context impacts ongoing visual and semantic processes. This will be addressed through lab-based studies and real-world neuroscience, which presents the ultimate test of how the environment changes our perceptions. I will deploy a range of cutting-edge methodologies; computational modelling, pattern similarity analysis, neural oscillations, connectivity, and augmented reality, within a convergent multimodal brain imaging framework (fMRI, MEG, EEG and mobile EEG). This research will drive forward models of object recognition, confronting the fundamental issue of how our perception of the world influences the dynamics of recognition.

Amount: £765,797
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cellular mechanisms of metabolic sensing by human hypothalamic neurons 06 Jun 2018

Obesity is a major public health problem, but its molecular mechanisms are poorly understood, frustrating efforts to develop broadly effective treatments. Obesity is characterised by abnormal energy homeostasis, which is regulated in large part by hypothalamic melanocortin neurons. The activity of melanocortin neurons is in turn regulated by circulating nutrients and hormones (e.g. leptin), but the mechanisms by which they sense and integrate these metabolic signals have been difficult to study using traditional model systems. Functional human melanocortin neurons derived from pluripotent stem cells provide an unprecedented opportunity to illuminate and therapeutically harness the molecular mechanisms by which human melanocortin neurons sense metabolic signals to regulate energy homeostasis. In particular, they enable a detailed characterisation of leptin signalling and direct testing of hypothesised mechanisms of leptin resistance. At a cellular level, the role of primary cilia in sensing and integrating leptin and other metabolic signals can be studied. Third, the synergistic action of different metabolic signals in vitro will be used to predict effective anti-obesity therapies in vivo. Together these studies will shed light on obesity disease mechanisms and facilitate the development of effective anti-obesity treatments.

Amount: £1,212,840
Funder: The Wellcome Trust
Recipient: University of Cambridge

Defining the biological basis of Staphylococcus aureus carriage 17 Jul 2018

Staphylococcus aureus is major cause of infection worldwide. This bacterium persistently colonises the nose (its natural niche) in around 20% of the population, which increases their risk of S. aureus infection. Why some people carry S. aureus while others never do is not understood, but is likely to reflect a complex trait influenced by multiple factors. This may include the human genome, host immunity, the nasal microbiota, bacterial-nasal epithelial cell interactions and lifestyle choices. We propose that key determinants for S. aureus carriage can be defined in a powered cohort study in which these parameters are established. Our study will capitalise on existing cohorts (INTERVAL & COMPARE) of healthy volunteers who have been extensively characterised through human genome sequencing and phenotypic profiling. We will screen 25,000 INTERVAL participants for S. aureus carriage, and using sequencing methods define their nasal microbiota composition. We will use existing as well as generate additional data on lifestyle. These datasets will be mined during a series of genome-wide and phenotypic association studies to identify factors that influence the nasal microbiota and S. aureus carrier status. Selected phenotypic and genetic variants of interest will then be tested in relevant experimental systems.

Amount: £2,341,255
Funder: The Wellcome Trust
Recipient: University of Cambridge

Nuclear genomic control of mitochondrial DNA heteroplasmy in humans: population genetics & disease 17 Jul 2018

Human mitochondrial DNA (mtDNA) mutates ~15-fold faster than nuclear genome, but only ~5% of the 16.5Kb mtDNA shows genetic variation in the population. Severe mtDNA mutations cause diseases affecting ~1 in 5000, but it is not known how new genetic variants arise, and why some are more common than others. We aim to address these two questions, building on pilot data implicating a mechanism acting on mtDNA during female germ cell development. Most humans inherit a mixed population of mtDNA (heteroplasmy) from their mother, and the proportion of mutated molecules can either increase or decrease within one generation due to a ‘genetic bottleneck’. This accelerates the segregation of alleles during early germ-cell development. We aim to: (a) define the mechanism of the bottleneck in germ cells; (b) identify the nuclear transcriptional signal controlling the bottleneck; (c) determine whether selection for/against particular mtDNA mutations occurs at the level of the cell, mitochondrion, or mtDNA molecule; and, (d) identify nuclear genes modulating the rate of segregation and selection. Together this work will define the fundamental biology driving mtDNA genetic variation in the human population, explain how this leads to mitochondrial diseases, and identity new approaches to prevent and treat these disorders.

Amount: £2,178,233
Funder: The Wellcome Trust
Recipient: University of Cambridge

Proteomic characterisation of secreted antiviral factors in cell-mediated immunity to human cytomegalovirus 30 Sep 2018

Human cytomegalovirus (HCMV) is a widespread human pathogen, infecting 60-80% of the population. Infection is asymptomatic in immunocompetent individuals but causes disease in immunocompromised patients, such as transplant recipients. Current therapeutic tools are limited, with no available vaccine and a limited array of antivirals. HCMV triggers a broad and robust immune response involving both the innate and adaptive immune systems. Antiviral immunity is mediated in part by proteins secreted by immune cells and infected cells. In order to counteract this immunity, HCMV encodes numerous evasion factors that modulate the function of immune cells and the array of proteins they secrete (‘secretomes’). In this project, I will apply mass-spectrometry to generate comprehensive profiles of the secretomes produced by different immune cells when exposed to HCMV-infected cells. Using this technique, it will be possible to identify important and potentially novel secreted antiviral factors that can subsequently be validated and investigated to determine their mechanism of action. This will contribute to a better understanding of HCMV immunity and may facilitate the design of novel effective vaccine candidates and therapies.

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

Statistical Methods for the Analysis of Deep Sequenced Pneumococcal Data 30 Sep 2018

Streptococcus pneumoniae (the pneumococcus) is a major disease causing pathogen and can cause sepsis, meningitis and pneumonia especially in at risk populations such as young children and the elderly. Understanding genetic factors in disease virulence, transmissibility, and drug resistance informs the management and treatment of infectious disease. By using deep sequenced patient samples of S. pneumoniae it is possible to build a clearer picture of its within host diversity. I aim to develop statistical and computational methods for the analysis of deep sequenced pathogen data that are also able to deal with large datasets, of the order of thousands of samples. I aim to apply these methods to the analysis of deep sequencing data derived from nearly 4000 S. pneumoniae samples taken from patients in the Maela refugee camp, Thailand. The methods I develop will help to identify significant genetic factors for disease dynamics and antimicrobial resistance. The project will contribute to the understanding of S. pneumoniae and will also provide tools of more general applicability to the investigation of deep sequenced pathogen data.

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

The effect of nutrients on maximal fat oxidation rates in adult humans measured using indirect calorimetry. 31 May 2018

I aim to study the effects of nutrient availability and mitochondrial transport capacity on the variability of maximal fat oxidation (MFO) during exercise in healthy adults. Less than half of MFO can be predicted by variables such as gender, VO2max and body composition. There are two possible reasons for this. First, nutrient availability may have a large effect on MFO and current protocols may not adequately control for it. Second, VO2max - which combines two variables with opposite effects on MFO (oxygen uptake and fat mass) - may not be the optimal predictor. Here, I will test whether heart rates at a given power are a better predictor of MFO and whether short-term fluctuations in nutrient availability can explain some of the variability of MFO seen within the general population. Nutrient availability will be altered using a glucose meal and by glycogen depletion. I will also use nitrate supplementation to test whether MFO can be increased by induced-expression of fat oxidation enzymes. The key goals are to determine to what extent short-term changes in nutrients and the expression of fat oxidation enzymes can alter MFO and whether the resultant fat oxidation rates can be predicted using simple heart rate data.

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