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Recipients:
University of Cambridge
University of Oxford

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

Serine ADP-ribosylation in genome stability and human disease 10 Apr 2018

ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and their mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as a previously unknown PTM. We showed that Ser-ADPr synthesis is dependent on histone PARylation factor 1 (HPF1), a recently identified specificity factor and interactor of DNA repair PARPs - PARP1 and PARP2. We further showed that Ser-ADPr specifically targets proteins involved in the maintenance of genome stability. Finally, we also revealed that a hydrolase called ARH3 acts as specific enzyme for a timely reversal of Ser-ADPr. Our first goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1 and ARH3 work in the synthesis/removal of Ser-ADPr. Our second goal is to define the physiological processes controlled by Ser-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.

Amount: £2,074,702
Funder: The Wellcome Trust
Recipient: University of Oxford

Expanding the Inventory Records and Online Profile of Early Modern Medical Books at the Science Museum 18 Jun 2018

The short-term goal of my six-month project is to create a new inventory of the Science Museum’s 158 pre-1800 medical books which would contain more up-to-date, detailed information about the contents, physical format and publication circumstances of the predominantly Latin and English codices. I also intend to explore and document links between the books and the museum’s large collection of medical objects. My project will also contribute to the long-term goal of making the books more accessible by the museum’s online search platforms. Consequently, part of my project may involve developing contextual materials to accompany the books, such as more in-depth, accessible information about the authors, the broader concepts they are engaging with, and their place within the history of medicine. I would also be keen, if possible, to increase the online presence of these books by writing a short, informal and engaging article aimed at the general public for the Science Museum Blog, or a more formal article on the process of cataloguing them for the Science Museum Group Journal.

Amount: £13,005
Funder: The Wellcome Trust
Recipient: University of Oxford

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

Modelling the impact of poor quality antimicrobials on patient outcome and drug resistance – a pilot study to inform policy in the absence of empirical data 30 Sep 2017

Antimicrobial resistance (AMR) is an increasingly serious and pressing global public health problem. Poor antimicrobial quality is increasingly realised as an important rectifiable impediment to global public health. There has been little discussion or evidence as to its comparative importance, in relation to other drivers such as poor prescribing and adherence, for both poor patient outcomes and AMR. In the absence of field data on the relationship between AMR and antimicrobial quality, mathematical modelling based on pharmacokinetic-pharmacodynamic relationships and rates of genetic change provides estimates which can be used to predict outcomes and inform policy. We propose a two phase modelling approach examining how poor quality essential medicines may affect patient outcomes and resistance selection and spread, modelling in Phase 1 antimalarials and in Phase 2 anti-tuberculosis and anti-hepatitis C medicines. This pilot project will build on the existing Wellcome investment in the Mahidol Oxford Research Unit (MORU) Network (though core funding) and the Infectious Diseases Data Observatory (through the MAPQAMP Biomedical Resources grant and core funding) for modelling, PK/PD and medicine quality resources and skills. The growing interest in medicine quality by nations and international organisations and the invitation by the WHO Member State Mechanism (on medicine quality) to the IDDO/MORU Medicine Quality Group to be a stakeholder, facilitates synergistic discussions with multiple partners and nations. We are also discussing expanding our collaboration with the United States Pharmacopeia PQM program on medicine quality & AMR. We are organising the first Conference on Medicine Quality & Public Health for September 2018 and we intend that the initial results from this work would be presented at this meeting. This project will therefore give the first objective evidence, rather than opinion, on the importance, or otherwise, of medicine quality on patient outcome and AMR, in comparison to poor adherence and poor prescribing. It will link in extremely well with the diverse activities of the MORU Network, IDDO, WHO, USP and diverse other stakeholders and be opportune for influencing policy for both medicine quality and AMR. This project will be linked to the parallel project proposed to Wellcome by Dr Elizabeth Pisani on ‘Understanding the political barriers to tackling sub-standard and falsified medicines’.

Amount: £99,994
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the functional role of GABA across the human motor network 05 Dec 2016

Understanding the functional role of GABA across the human motor network

Amount: £214,011
Funder: The Wellcome Trust
Recipient: University of Oxford

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

Novel statistical methodology for rare variant association in a case-control cohort 30 Sep 2018

Genetic association studies focusing on common variation have uncovered only a fraction of proposed trait heritability. Some of this so-called missing heritability will be found within rare variation in the population. This hypothesis is supported by the facts that recent explosive population growth has increased the population burden of rare variants and deleterious variants are kept at low allele frequencies. All genetic susceptibility to disease is caused by alterations to the genes or their expression and for this reason it seems fruitful to focus an association study on the genes themselves. Any associations found are then directly informative about the molecular basis of disease without the need for fine mapping. The proposed project aims to develop a statistical method to find genes associated with disease by analysing the rare variation present in a case-control cohort. We aim to extend existing methods by including a previously unconsidered parameter; the position of the variants in a gene. In scenarios where differences in clustering or distribution of variants are observed between cases and controls, this method will have a substantial increase in power. This technique will be useful for elucidating the molecular mechanisms causing the disease and thus discovering new therapeutic targets.

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

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

Design and evaluation of a modified vaccinia Ankara vector therapeutic vaccine for hepatitis B immunotherapy 30 Sep 2018

Hepatitis B virus (HBV) is a serious global health problem, with approximately 240 million people chronically infected. Long-term infection can lead liver failure, cancer and death. Current therapy controls but does not eradicate the infection. T cells are a type of immune cell necessary to fight HBV. During chronic hepatitis B these cells become less active. Checkpoint inhibitors are a form of immunotherapy that enables T cells to function again. In a study of woodchucks infected with a similar virus to HBV, treatment with vaccine and checkpoint inhibitor lead to better control of the virus. This project aims to use this combination of vaccine and checkpoint inhibitor, to treat patients with chronic HBV. A vaccine using a virus to carry the HBV proteins has been developed and shown to generate good immune responses in mice. We plan to develop a second vaccine to boost this response and test the vaccines together with checkpoint inhibitors in mice infected with the HBV virus. This will allow us to assess how effective this is at eradicating HBV. If the results from this study are promising, this could pave the way for clinical trials in humans with chronic HBV.

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

Probing nucleotide interactions with Kir6.2 using fluorescence spectroscopy. 30 Sep 2018

The ATP-sensitive potassium (KATP) channel is a plasma membrane protein present in beta cells of the pacreas which plays a key role in insulin secretion. KATP acts as a metabolic sensor, alerting the beta cells when blood glucose raises too high and stimulating them to release insulin. In diabetes, normal KATP function is disrupted and beta cells no longer secrete insulin properly in response to blood glucose levels. The molecular structure of the channel is closely linked to its function; there have been several genetic studies linking various mutations (which often only affect one molecule in the channel!) to neonatal diabetes or increased propensity to type II diabetes. Our research aims to identify precisely how these small mutations can have such drastic changes in the activity of the channel by using a combination of fluorescent labels and channel current measurements to watch the KATP channel move in real time. We can then try to construct a model of how the channel converts different stimuli into movements, and how this is affected in mutations linked to diabetes.

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

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