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Recipients:
University of Cambridge

Results

The Genetic Basis of Congenital Hypothyroidism 30 Sep 2018

I have already identified 2 novel genetic causal variants for congenital hypothyroidism (CH) by whole exome sequencing (WES); IGSF1 defects in central hypothyroidism and SLC26A7 in dyshormonogenetic CH. I will therefore continue this strategy to identify further genetic causes of CH. I will expand my CH cohort, enriched for probability of genetic mutations. After excluding candidate gene defects, cases will undergo WES. I will then undertake functional characterization of specific novel variant s using in vitro techniques and a zebrafish model of thyroid development. Human SLC26A7 mutations are a novel cause of dyshormonogenetic CH and the disorder or its pathogenesis has not been characterized; I will phenotype cases to define this syndrome in more detail. I will characterize the biological function of SLC26A7 (a key transport protein), by performing electrophysiological studies to define its role as a putative anion transporter in the thyroid. Structure-function relationships in S LC26A7 are poorly understood. I will therefore characterize the properties of naturally-occurring and artificial SLC26A7 mutants to define functional domains in this protein.

Amount: £214,297
Funder: The Wellcome Trust
Recipient: University of Cambridge

Resolving mesodermal diversification with single cell transcriptomics 30 Sep 2018

During the course of development, cells divide, migrate, and specialize to form major organ systems. Furthemore, among most mammals and birds, mouse cells differentiation follows a unique morphology. Understanding the molecular mechanisms underlying such process is a core issue in Biology and a curiosity in mouse, which despite differences still share fundamental properties during the process. The challenge has been addressed by leveraging current high-throughput technologies such as single cell transcriptomics. The amount and complexity of this data requires innovative mathematical frameworks that take advantage of current computational capacities. I am intersted on resolving mesodermal diversification during mouse gastrulation. Based on the premise that single cell profiles represent snapshot measurements of expression as cells traverse a differentiation process, I will use probabilistic modeling among other statistical and mathematical methodologies to reconstruct a measure of a cell’s progression through some biological process, and to model how cells undergo some fate decision and branch into two or more distinct cell types. In particular, Bayesian Inference has shown to be a useful approach to take advantage of computational resources, and to include prior knowledge into models, by providing a formal probabilistic framework that allows learning from the data in order to make predictions.

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

Cholera vaccine effectiveness in Nsanje and Chikwawa, Malawi 30 Sep 2018

Following the 2015 oral cholera vaccine (OCV) mass campaign of 160,000 people in Nsanje District, Malawi, the International Vaccine Institute (IVI) was funded to setup diarrheal disease surveillance in Nsanje and adjacent Chikwawa districts. Surveillance is ongoing at 22 and 18 health care facilitiesin Nsanje and Chikwawa, respectively. Research activities include to 1) analyse the vaccine effectiveness (VE) in Nsanje, through a 1:4 case-control study and 2) conduct a cost-of-illness study to help estimate OCV cost-effectiveness. The IVI is working in parallel in neighboring Mozambique. Diarrheal disease surveillance is ongoing in the Cuamba study area and an OCV has been conducted in 08/2018. The Mozambique study area borders the Malawian Nsanje/Chikwawa districts. We propose to continue the research in Malawi through extending the surveillance work and the case-control study, to ensure the assessment of long-term VE and cost-effectiveness. Further, the extent of herd protection through OCV needs to be assessed; the Chikwawa setting, after the 2018 OCV campaign constitutes the perfect scenario. The GFTCC is currently preparing a research agenda for "End cholera by 2030" roadmap and the Malawi/Mozambique scenario with surveillance ongoing in both countries, provides an unique opportunity to answer research questions identified through the GFTCC.

Amount: £155,986
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Schwann cell-axonal communication during axonal degeneration and regrowth 25 May 2017

Myelinating and non-myelinating Schwann cells are reprogrammed after nerve injury into repair Schwann cells, specialized for maintaining survival of injured neurons and supporting axonal regeneration. This process is regulated by Schwann cell-intrinsic signals, such as the transcription factor c-Jun, however few other candidates have been identified. It is, currently, unknown how Schwann cell reprogramming is initiated, but unidentified extrinsic signals from injured axons are likely candidates. I aim to delineate the spatial and temporal regulation of Schwann cell-intrinsic downstream signals in real-time and define their role in repair Schwann cell function and axonal regeneration. Secondly, I aim to test the hypothesis that axon-derived signals initiate Schwann cell reprogramming during nerve injury. I will use cell culture, in vivo mouse models and a live and dynamic zebrafish larval model of nerve injury. This study will be the first to investigate how axon-intrinsic mechanisms of nervous system injury interplay with glial cell molecular responses to nerve damage, in real-time. Using cutting edge techniques in two species, this project will significantly advance our understanding of Schwann cell-axonal biology and tissue repair. Excitingly, this research may identify new potential therapeutic targets to improve poorly regenerating human nerves and treat patients with neuropathies.

Amount: £426,876
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of Eros in Innate and Adaptive Immunity 30 Sep 2017

I will investigate the role of a novel protein, Eros, in immunity. I discovered the fundamental importance of this protein by demonstrating that Eros-deficient mice die from Salmonella infection because their phagocytes cannot make reactive oxygen species. This is because Eros is essential for expression of vital components of the phagocyte NADPH oxidase. My work represents the only paper on this protein. I have found that Eros-deficiency has effects that go far beyond the generation of reactive oxygen species. In particular: Eros regulates the expression of other key macrophage proteins including P2X7, a key activator of the NLRP3 inflammasome Eros regulates the expression of numerous cytokines from CD4+ T cells. Eros -/- T cells make 10-fold more IL-4 than control cells In mouse and human systems, I will investigate the molecular mechanisms by which Eros: controls the abundance of a subset of proteins working on the hypothesis that it is a novel component of the protein quality control pathway using structural, biochemical and cell biological techniques. controls T cell cytokine secretion. I will spend time working with John O'Shea, a world leader in this field.

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia 06 Dec 2016

Secondary pneumonia following influenza infection is common, with considerable associated morbidity and mortality. Strikingly, secondary infections tend to arise from bacteria which live otherwise asymptomatically in the oropharynx. Based on existing data, I hypothesise that the development of secondary streptococcal pneumonia is dependent on a key immune-cell molecular pathway, namely Phosphoinsitol-3-Kinase delta (PI3Kdelta), and that inhibition PI3Kdelta will be protective via the following mechanisms. 1) Influenza-induced expansion of immunosuppressive regulatory T-cells (Treg) which depend on PI3Kdelta for suppressive functioning 2) Viral and Treg mediated suppression of neutrophil function 3) A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by Streptococcus pneumoniae. The goals are: 1) To determin whether PI3Kdelta-null animals are resistant to secondary streptococcal pneumonia. 2) To use tools including Treg depleted animals, conditional knockout animals and small molecule PI3Kdelta inhibitors to explore mechanisms of resistance. 3) To develop a more clinically relevant murine model secondary pneumonia, using a streptococcal colonisation model which when exposed to influenza will develop secondary pneumonia. 4) To characterise the respiratory microbiome of animals at various stages will be characterised, looking for factors that may facilitate or militate against development of secondary pneumonia.

Amount: £516,560
Funder: The Wellcome Trust
Recipient: University of Cambridge

21st Century Families: Parent-child relationships and children's psychological wellbeing 25 Jul 2017

New pathways to parenthood have recently emerged that did not exist, nor had even been imagined, at the turn of the 21st century. Individuals who were previously unknown to each other have begun to meet over the internet with the purpose of having children together; transgender men and women have begun to have children through medically assisted reproduction; single heterosexual men have begun to use surrogacy to become single fathers by choice; and women have begun to use identifiable egg donors to have children. These emerging family structures raise new ethical, social and psychological concerns, particularly regarding the potentially negative consequences for children. The proposed research will provide empirical evidence from a multidisciplinary perspective on the social and psychological consequences for children of growing up in family arrangements involving non-cohabiting co-parents, transgender parents, elective single fathers and identifiable egg donors. In this emotive area of family life on which people often hold strong opinions, our aim is to challenge prejudice and assumption with evidence on the actual consequences – good, bad or neutral – for children. The ultimate goal of the proposed research is to increase understanding of diversity in family life and improve the lives of 21st century children.

Amount: £1,552,401
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biomechanics of Ciliated Tissues 11 Jul 2017

Many of the paradigmatic events in embryonic development involve geometric or even topological rearrangements of tissues in response to mechanical forces generated within them. While these processes are familiar and much studied from genetic and biochemical perspectives, there is a striking contrast between the great depth of such biological detail and the glaring lack of quantitative mechanical understanding of the forces and responses involved. We propose to close the theory-experiment loop in specific, carefully chosen examples of these problems, to gain a quantitative understanding of the underlying biomechanics. We seek to solve three outstanding problems: (i) the link between cell shape changes and cell sheet morphology as found in gastrulation, neurulation, and related problems in embryogenesis; (ii) the mechanism of generation of cilia orientational polarity in tissues; (iii) the origin of metachronal wave formation in carpets of cilia. The research will combine state-of-the-art light-sheet microscopy, micromanipulation, high-speed imaging and microfluidics with emerging theoretical tools for understanding complex geometrical transformations of tissues and the stochastic nonlinear dynamics of eukaryotic flagella.

Amount: £1,656,325
Funder: The Wellcome Trust
Recipient: University of Cambridge

Epigenetic inheritance: the influence of variable silencing of the repeat genome. 10 Apr 2018

Evidence from epidemiological studies and experiments in animal models suggests that effects of environment and lifestyle can be transmitted across generations via non-genetic mechanisms. Such mechanisms are challenging to unravel in mouse and man. In mammals, non-genetic inheritance is best exemplified by the Agouti viable yellow (Avy) mouse where phenotypic differences in genetically identical animals are caused by insertion of a retrotransposon - an endogenous retrovirus (ERV) that provides a cryptic promoter driving ectopic expression of agouti. This ERV is variably DNA methylated in different individuals causing inter-individual variation in coat colour – a non-genetic influence on phenotype. Remarkably, a memory of parental coat colour is transmitted to subsequent generations. Variable expressivity can be modulated by in utero environmental exposures. ERVs represent ~12% of the mouse genome. Inspired by Avy, we propose a research programme, supported by preliminary data, to address the following questions: Aim 1 – To what extent do mammalian ERVs exhibit variable epigenetic silencing and what is the mechanism? Aim 2 – Is this transmitted as non-genetic memory across generations? Aim 3 – Are they sensors of environmental compromise? Aim 4 – Are there implications for phenotype? Aim 5 – Does a related phenomenon occur in humans?

Amount: £2,929,851
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding the Initiation of Viral Replication & its Role in Influenza Virus Pathogenicity 31 May 2018

The development of novel strategies against influenza viruses depends on our understanding of influenza virus replication and pathogenicity. Both are directly linked to the activity of the viral RNA polymerase, which copies and transcribes the viral genome, and generate aberrant RNA products that are non-contiguous in the viral genome and strong inducers of the interferon response. Despite recent crystal structures of the RNA polymerase, we only poorly understand how it interacts with and copies the viral genome, or how it generates aberrant RNA products. This project aims to use i) structure-guided mutagenesis, ii) in vitro and in vivo activity assays, iii) cell culture-based interferon production assays, to ask if RNA polymerase residues that bind and guide the viral genome are important for the initiation of viral replication and the formation of aberrant RNA products and thereby the pathology of influenza virus infections. The project will contribute to our understanding of the mechanics of influenza virus replication and the identification of putative targets for the development of new anti-influenza virus drugs.

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

Modeling cell differentiation dynamics from single cell genomics data 30 Sep 2018

We aim to understand in detail the dynamics of how white blood cells (specifically T helper cells) react to infections by multiplying rapidly and at the same time adapting their cell state to fight the infection. In particular, we focus on a mouse model of malaria where T helper cells differentiate into two subtypes: Th1 and Tfh. By quantitatively profiling the T helper cell population at different time points during a malaria infection, we expect to improve our understanding of the mechanisms which are responsible for the cell proliferation and specialisation. We study the cell population by detecting RNA expression, surface markers and cell divisions at the single cell level. The RNA expression will provide clues as to genes which are driving this process, and we will test a subset of genes using CRISPR knock outs. In addition to a better knowledge of the immune system, we hope to develop new mathematical and computational methods that will be widely applicable to modeling cell proliferation and differentiation data in diverse biological contexts.

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

Metabolic magnetic resonance imaging across the human heart 18 Oct 2017

During my fellowship, I proved the feasibility of measuring cardiac energetics in volunteers and patients using ultra-high field (7T) MRI scanners. The sensitivity and the separation of signals from different metabolites both improved significantly compared to standard research scanners. I recently secured £340k funding to fit a new phosphorus coil on the Oxford 7T scanner, which I am now testing in volunteers. Theory predicts that this coil will have several complementary technical advantages. These will enable mapping of cardiac energy metabolism across the whole heart, with sufficient spatial resolution to distinguish signals from healthy from diseased tissue. It will also enable quantification of cardiac energy metabolism with high precision to study single subjects rather than groups. I request funding to validate these new whole-heart methods, proving their value in three carefully-targeted groups of patients, via an extension of my fellowship. My goals are (A) to study patients in which the metabolic pattern is known by other means; (B) others where the metabolic pattern will reveal previously-inaccessible aspects of disease mechanism; and (C) to prove I can resolve metabolic changes in single patients. Success in each of these studies will give me the pilot data needed for competitive Senior Fellowship applications.

Amount: £584,259
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

Protein level knockdown of transmembrane proteins 31 May 2018

TrimAway is a newly described protein-level depletion method for degrading specific endogenous proteins. The technique relies on the experimental introduction of antibodies to the cell, which elicits rapid degradation of target antigens via the cytoplasmic Fc receptor and E3 ubiquitin ligase TRIM21. This enables acute depletion of proteins, enabling the functional characterisation of previously intractable proteins. TrimAway has been shown to act against diverse cytosolic substrates including membrane-anchored GFP. However, it is currently unknown whether TrimAway is capable of targeting transmembrane proteins. To address this, we will attempt to degrade three representative transmembrane proteins using TrimAway. With one, seven and twelve transmembrane passes respectively, the impact of topology on degradation rates will be determined. Targets, and control GFP, will be expressed as C-terminal myc-tagged constructs and expressed in human cells competent for TrimAway. Anti-myc antibody will be electroporated into the cells according to established protocols and the fate of target proteins will be monitored by western blot. Our targets have been selected as well-studied, disease-relevant proteins whose function may be illuminated by acute depletion. The results will help define the limits of the TrimAway technique and shed light on the cell's ability to degrade membrane proteins via the ubiquitin-proteasome system.

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

Investigating the Contribution of SOX17 Mutations to the Pathogenesis of Pulmonary Arterial Hypertension 30 Sep 2018

Pulmonary arterial hypertension (PAH) is a rare fatal disease characterised by increased medial muscularisation of larger pulmonary arteries and neomuscularisation of small non-muscular arterioles, leading to obliteration of the vessel lumens. This increases the pulmonary arterial pressure and thus, the workload placed on the right ventricle, ultimately causing death by right ventricular failure. PAH is associated with endothelial dysfunction, namely increased permeability and apoptosis. Mutations in the gene encoding the Bone Morphogenetic Protein type II receptor, BMPR2, cause the majority of familial PAH cases and approximately 25% of apparently sporadic cases. Recently, we have co-ordinated a national DNA sequencing study of patients with idiopathic PAH to identify causal genetic mutations. Our study has identified that mutations in the gene, SOX17, are significantly associated with PAH in some IPAH patients. SOX17 is a transcription factor that is reported to control endothelial function during developmental angiogenesis, integrating with vascular endothelial growth factor signalling. We have identified a potential link with BMP signalling, whereby circulating BMP ligands that regulate endothelial stability induce the expression of SOX17. My project aims to explore the role of SOX17 in the pulmonary circulation and how SOX17 deficiency may cause dysregulated pulmonary vascular function.

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

Building and breaking epithelial integrity in the neural tube: an optogenetic approach 18 Oct 2017

Using an innovative optogenetic approach within the zebrafish neural tube, I will directly explore how the polarity of individual cells drives the tissue organisation of a whole organ. In combination with 4D live imaging and functional abrogation, I will use light to specifically and reversibly manipulate apicobasal polarity, cleavage furrow formation and PI3K pathway signalling on a subcellular level. I will assess how apicobasal polarity and division are interrelated during morphogenesis of vertebrate epithelial tubes and how this relationship contributes to tissue integrity. Early zebrafish neuroepithelial divisions are highly predictable and coincident with de novo apicobasal polarisation. This provides a tractable model to assess a potential feedback loop between apical protein localisation and cleavage furrow positioning during epithelial establishment. The PI3K pathway is likely key to integrating apicobasal polarity with division. Within established epithelia, PI3K pathway defects are prevalent in cancers. I will manipulate PI3K pathway signalling within individual cells or groups of cells within an otherwise normal zebrafish neural tube. This in vivo method for manipulating cancer-linked signalling will allow me to test whether apicobasal polarity dysregulation is a cause or consequence of tissue disruption, providing clues to the cellular mechanisms of disease initiation.

Amount: £977,448
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fractionating the human frontoparietal cortex: combining meta-analytic and real-time optimization approaches 08 Nov 2017

Disruptions in the same set of frontal and parietal brain regions are seen across a striking range of psychiatric and neurological conditions. This network of regions has been referred to as multiple-demand (MD) system and can be divided into at least two closely coupled subnetworks. However, despite extensive research efforts, the specific functional mechanism each subnetwork supports remains poorly understood using available neuroimaging technology. To overcome these limitations, I have recently developed a novel technique based on real-time neuroimaging and machine learning: Neuroadaptive Bayesian Optimization (NaBO). The key goal of this fellowship is to develop a complementary approach that leverages the strength of large-scale, automated meta-analyses and NaBO to obtain a fine-grained functional mapping between MD subnetworks and the cognitive processes they support. This approach will exploit the wealth of data generated by neuroimaging to date (meta-analysis) for defining a prior model of how cognitive functions relate to MD subnetworks and then refine this model in unprecedented detail (NaBO). The resulting model will be validated using behavioural assessment. Advancing our understanding of these subnetworks in normal brain function is an important first step for developing targeted clinical interventions and informing the design of sensitive diagnostic test batteries.

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

The role of RNA modifications in myeloid leukaemogenesis 24 Apr 2018

Acute myeloid leukaemia (AML) is a devastating cancer with a long-term survival below 30% for which mainstream treatments remain unchanged for several decades. Advances in genomics have highlighted the importance of epigenetic corruption in both initiating and maintaining the disease, making the epigenome an important therapeutic focus. Recently, using CRISPR-Cas9 recessive genetic screens, we identified several RNA-binding/modifying proteins as essential for AML cell survival. We have since confirmed that the RNA methyltransferase METTL3 is required for AML maintenance through its role in co-transcriptional N6 adenosine methylation of target RNAs, but is dispensable for normal haematopoiesis proposing it as a novel "druggable" therapeutic target in AML (Barbieri, Tzelepis et al, Nature 2017). Here, I propose to extend the investigation of the epitranscriptome as a new therapeutic focus in AML by studying promising AML-essential RNA-binding/modifying proteins, including METTL1 and METTL16, using unique reagents and expertise as well as access to clinically relevant bespoke models and human samples.

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