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Results

Cellular Dynamics and Regulatory Networks Controlling Endometrial Remodelling during the Window of Implantation 17 Jul 2018

The endometrium undergoes iterative cycles of menstrual shedding, regeneration, rapid growth, and differentiation in response to ovarian hormones. During the mid-luteal phase, the endometrium becomes transiently receptive to implantation, heralding the start of a process of intense tissue remodelling, characterized by secretory transformation of glandular epithelium, angiogenesis, differentiation of stromal cells into secretory decidual cells, and activation of specialized immune cells. Several reproductive disorders, including recurrent pregnancy loss, are linked to defects in tissue remodelling at implantation. However, the cellular complexity and dynamic nature of the endometrium have so far precluded precise characterization of the underlying pathological mechanisms and drivers. We will employ high-throughput single-nucleus sequencing to map the dynamic changes in gene expression and chromatin accessibility (cis-regulatory regions) in all endometrial cell types across the luteal phase in defined patient groups. The data will be back-mapped to a future successful pregnancy or miscarriage. This analysis will yield unparalleled insight into the sequence of endometrial events (i.e. changes in cell populations, cellular states, gene expression and transcriptional regulation) leading to a successful or failed pregnancy. Further, 3D organoid cultures, consisting of glands and stroma, will be used to investigate putative drivers of endometrial dysfunction and to evaluate new treatment targets.

Amount: £1,281,629
Funder: The Wellcome Trust
Recipient: University of Warwick

Structure and mechanism of a key bacterial cell division protein 06 Sep 2018

To divide and multiply, bacteria must remodel their cell envelope to facilitate physical separation of daughter cells. FtsEX is a key player in coordinating cell division events on either side of the bacterial inner membrane. FtsEX belongs to the same protein superfamily as the MacB efflux pump and the LolCDE lipoprotein trafficking complex, collectively termed Type VII ABC transporters. Current models for FtsEX activity suggest long range conformational changes in FtsEX regulate periplasmic enzymes responsible for peptidoglycan hydrolysis while maintaining cytoplasmic interaction with the septal Z-ring. Structural and functional data are essential to understand how FtsEX works and to assess viability of inhibition using chemical compounds. This project seeks to characterise the interaction of FtsEX with its binding partners, the role of ATP binding and hydrolysis, and to obtain structural data using X-ray crystallography. The project builds on published work on Type VII ABC transporters and is supported by preliminary data showing FtsEX has been crystallised. The Seed Award will presage future applications to the Wellcome Trust, MRC or Leverhulme Trust to further explore the structure and function of bacterial cell division proteins as targets for future antibiotic development.

Amount: £98,945
Funder: The Wellcome Trust
Recipient: University of Warwick

Transformations: Encountering Gender and Science 16 Jun 2018

The Rethinking Sexology team’s historical research has uncovered important material on the relationship between medical authority and ‘patient’ experience and the development of diagnostic categories/treatment protocols. We propose a public engagement programme that invites young trans people (age 16-25) to explore this material, co-conduct new research, including an oral history project, and develop an ambitious programme of creative responses leading to a performance and exhibition in four relevant high-profile venues across the UK. The plan of action has been developed during an extensive consultation period with key stakeholders, in which ideas and methodologies have been fully tested. The programme is led by the Rethinking Sexology (RS) team who has an outstanding track record in field-leading engaged research and public engagement. The team’s experience will be complimented by collaborating with a uniquely qualified group of writers, performers and youth-facilitators, known for their pioneering and award-winning work with the trans community, with whom the RS team already has long-standing collaborative relationships. The programme will deliver a set of exceptionally innovative activities that will empower young people to: contribute to and enhance health and humanities research and public engagement practices; investigate clinical and diagnostic protocols and transform clinical dialogue; shape public debate through high-quality creative outputs (exhibition/performance) that promise to be intellectually, artistically and emotionally powerful and stimulating. The co-production model at the heart of the programme will feed systematically and continually into ongoing research activities, enabling the project to stand as a beacon of good practice in engaged research and public engagement.

Amount: £147,315
Funder: The Wellcome Trust
Recipient: University of Exeter

Connexin 32 evolution to a CO2 sensor 31 May 2018

Connexin26 (Cx26) is the CO2 chemosensor from reptiles to humans. The CO2 sensitivity of Cx26 arose early in the evolution of air breathing and is present in the ancient lungfish ancestor of all tetrapods. However, Cx26 of modern ray-finned fish has lost the CO2-binding motif. In mammals, Cx32 has a CO2 binding motif almost identical to that of Cx26 and is also sensitive to CO2. Strikingly the CO2 binding motif is retained in Cx32 of ray-finned fish. I would like to test the hypothesis that Cx26 and Cx32 have evolved from a common ancestor. An important step in testing this hypothesis is to see whether Cx32 of different ray-finned fish species is sensitive to CO2 and compare the protein sequence similarity. I will transfect fish Cx32 cDNA into HeLa cells and use a simple dye loading assay to test their CO2-sensitivity. I will also quantify the CO2 sensitivity of human Cx32 to give a direct comparison between fish and human Cx32. I will conduct a bioinformatic analysis of Cx32, paying particular attention to the CO2-binding motif, from several fish, amphibian, reptilian and mammalian species. My work will shed new light on the origins of CO2 binding in the connexin family.

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

Diabetic Vascular Disease (DVD): Enhancing our understanding of the cause of DVD 31 May 2018

The two main forms of diabetes are type I and type II diabetes; type I is an autoimmune disease where the insulin producing beta cells are destroyed by the body’s own immune system, and as a result the body cannot produce insulin. Type II, the most common form of the disease accounts for 90-95% of all diabetes. Both types lead to hyperglycaemia and insulin resistance. These causes overproduction of reactive oxygen species (ROS) and via endothelial dysfunction and inflammation, this accumulation of ROS plays a major role in precipitating diabetes vascular diseases (DVD) in these patients. If DVD is not treated the blood vessels will continue to narrow and will eventually become occluded by the deposits of fat. This will lead to ischaemia in the organ which can be fatal if this occurs in the brain or heart. Our overall aim is to better understand DVD at a molecular level and how it is actually caused, and this will be achieved by studying endothelial cells and exposing them to DVD inducing factors and see how they change.

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

Macromolecular Mechanisms of Microsporidia Infection Investigated by Cryo Electron Tomography 21 May 2018

Microsporidia are eukaryotic, intracellular parasites that infect most animals, including humans. They cause debilitating disease in immunocompromised individuals and are partly responsible for the global decline in honeybee populations. To infect a host cell, microsporidia employ a harpoon-like apparatus called polar tube (PT) that rapidly ejects from the spore, penetrates the membrane of a target tissue cell and transports the spore content (sporoplasm) into it. I propose to investigate the so-far unknown macromolecular architecture and mechanism of the PT using state-of-the-art cryo electron tomography (cryoET). The key goal is to examine the cellular machinery that facilitates PT release, sporoplasm transfer and target membrane penetration. This research will provide 3D molecular maps of the PT in action and thus detailed and dynamic understanding of the microsporidian infection pathway. The research will enrich our knowledge of fundamental cell biology, establish microsporidia as a eukaryotic model system for cryoET, inform new medical approaches to treat microsporidiosis and help fight the decline in honeybee populations. Seed Award funding will pave the way for my career as new independent group leader in the UK, with a high impact biomedical profile and will offer a plethora of opportunities to collaborate with academia and industry downstream.

Amount: £98,680
Funder: The Wellcome Trust
Recipient: University of Exeter

Probing the chromatin assembly pathway 18 Oct 2017

Histone deposition to form nucleosomes is an important process underlying all genomic transactions. Research over the last 20 years has put forward the idea of a dedicated histone chaperoning pathway in which histones are transferred between a number of distinct chaperoning complexes that guide their thermodynamic assembly into nucleosomes. This has been difficult to test directly with the currently available toolset for pulse labeling of proteins. Furthermore, mixing of soluble nuclear proteins with cytosolic extracts upon cellular fractionation has complicated defining the nucleo-cytoplasmic division within the pathway, at least through biochemical means. I have recently developed a new approach for pulse-chase labeling of nuclear proteins using a cytosolic tether-and-release strategy that offers some advantages in studying the early stages of the histone chaperoning pathway, which I plan to capitalize on. I also aim to understand in greater detail at the molecular level the interplay between two chaperoning proteins that have been shown to be important in H3-H4 heterodimer formation. My key goals are to (1) investigate the early stages of histone processing, (2) investigate the molecular basis of interaction between sNASP and the H3-H4-ASF1 complex and (3) further develop tether-and-release approaches to investigate fast kinetics of nuclear proteins.

Amount: £921,866
Funder: The Wellcome Trust
Recipient: University of Warwick

The development of insulin resistance and anabolic resistance during muscle disuse: what is the role of fuel integration? 08 Nov 2017

Skeletal muscle atrophy, which occurs during short-term disuse, is thought to be due to the development of anabolic resistance of protein metabolism and insulin resistance of glucose metabolism, although their cause is currently unknown. The primary research aim of this fellowship is to establish the role of muscle fuel availability and integration in disuse-induced insulin and anabolic resistance. In collaboration with the Medical School, I will perform two randomized, placebo-controlled studies in which young, healthy participants undergo 2 days of forearm immobilisation with placebo, Acipimox (to decrease plasma lipid availability), Formoterol (to stimulate glycolytic flux), or dietary branched-chain amino acid (BCAA) manipulation, to alter substrate availability. I will combine the arteriovenous-venous forearm balance technique, that I have recently established in Exeter, with stable isotope amino acid infusion and repeated forearm muscle biopsies to quantify muscle glucose, fatty acid, and BCAA balance, oxidation, and intermediary metabolism (including muscle protein synthesis), both fasted and during a hyperinsulinaemic-euglycaemic-hyperaminoacidaemic clamp. Two periods of research at the University of Texas Medical Branch will enable me to develop skills in mass spectrometry tracer analyses and develop a network of collaborators in the USA, both crucial for my future career investigating disuse-induced muscle atrophy.

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

Shedding light on platinum chemotherapy: a new mechanistic approach 08 Nov 2017

Despite their widespread clinical use in cancer treatment, platinum(II) complexes, including cisplatin, present critical issues such as severe side effects and onset of resistance. Furthermore, their mechanism of action is not fully understood and no reliable patient stratification tool exists. Novel prodrugs based on photoactivatable platinum(IV) complexes are reduced to cytotoxic platinum(II) species upon irradiation with visible light, providing spatial control of their cytotoxicity. Photoactivated complexes are active in cisplatin-resistant cell lines suggesting a different mechanism of action. I will investigate the mechanism of action of platinum-based anticancer drugs on- and off-target, with focus on photoactivatable complexes and clinically established drugs. The cellular targets will be identified by functional genetics experiments (RNAi/CRISPR-Cas9 screening) and the fate of platinum in vivo will be evaluated by SPECT imaging with platinum-195m labelled complexes in mouse xenograft cancer models (Goal 1). The positron-emitting isotope copper-64 will also be used to evaluate copper-transporter Ctr1 as a biomarker to predict response to platinum-based chemotherapy (Goal 2). Based on these findings, I will modify photoactivatable platinum(IV) complexes (i) to reduce their off-target toxicity by attachment to antibodies targeting specific cancer-cells receptors and (ii) to enhance cytotoxic effect upon photoactivation, by attachment to light-harvesting chromophores (Goal 3).

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

Neurobiological mechanisms of emotional relief in adolescents with a history of sexual abuse 06 Dec 2017

Adolescents who experienced childhood sexual abuse (CSA) engage in non-suicidal self-injury (NSSI) more frequently than peers exposed to other forms of abuse or no abuse. NSSI serves an important function of relief from acute negative affect. Despite providing temporary relief from distress, NSSI is also linked to higher rates of suicide and hospitalisations and the effectiveness of current clinical interventions is limited. This may be attributed to a lack of understanding the neurobiological and behavioural mechanisms that underlie NSSI as a relief function in particular in youth who experienced CSA. To address this gap, the study aims (1) to model brain activity during distress and emotional relief (i.e., NSSI) in adolescents with and without a history of CSA using functional magnetic resonance imaging and (2) to examine if adolescents with CSA select actions to 'escape' an aversive context more quickly and often compared to non-abused peers. The ultimate goal of this translational research is to understand the neurobiological and behavioural mechanisms that confer vulnerability to NSSI following CSA (Stage 1) in order to develop effective intervention and prevention strategies to keep vulnerable teenagers safe (Stage 2) . Keywords: sexual abuse, non-suicidal self-harm, relief, functional magnetic resonance imaging, translational research

Amount: £230,048
Funder: The Wellcome Trust
Recipient: University of Exeter

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £58,344
Funder: The Wellcome Trust
Recipient: University of Exeter

Open Access Award 2017/18 30 Sep 2018

Not available

Amount: £42,025
Funder: The Wellcome Trust
Recipient: University of Warwick
Amount: £4,000
Funder: The Wellcome Trust
Recipient: University of Warwick

Analysing the chromatin and transcriptional landscapes controlling endoderm cell fate decisions during zebrafish embryogenesis 04 Dec 2017

The endoderm germ layer of the vertebrate embryo makes major contributions to the respiratory and gastrointestinal tracts, and all associated organs. The key goals of this project are to exploit the advantages of zebrafish to: 1. Investigate heterogeneity of gene expression amongst endodermal progenitors prior to mature organ formation to define discrete expression patterns controlling development of distinct endodermal tissues in vivo. 2. Characterize dynamic expression patterns controlling emergence of distinct progenitor populations. 3. Identify genomic cis-regulatory modules controlling expression of key lineage-specific genes. 4. Develop multi-purpose fluorescent reporter and Cre-driver transgenic lines to facilitate future detailed study of specific lineages throughout organogenesis. Aims 1 & 2 will be achieved through single-cell RNA-seq characterization of thousands of cells isolated using pan-endodermal Tg(sox17:GFP) transgenic line at multiple timepoints between gastrulation and budding of endodermal organs, followed by detailed bioinformatics analyses. Aim 3 will be achieved through ATAC-seq characterization of chromatin accessibility at identical developmental stages. Aim 4 will be achieved by molecular cloning of putative cis-regulatory modules revealed by ATAC-seq for single-cell RNA-seq candidate genes followed by Tol2 transposon transgenesis. The output will be more detailed understanding of endoderm cell fate regulation and novel transgenic lines to seed future projects and grant applications.

Amount: £99,998
Funder: The Wellcome Trust
Recipient: University of Warwick

The filamentous phage assembly system as a therapeutic tool 04 Dec 2017

Antibiotic resistance is a growing healthcare concern worldwide. The rise in the number of resistant bacteria is not being matched with an increase in new antibiotics or treatments. Novel ideas harnessing modern technology therefore need to be applied to address this problem in a timely manner. In this work, a phage encoded assembly system will be assessed for its potential application as a "switch" to control bacterial proliferation. By genetic manipulation of cells and viruses, protein expression, purification and high-end electron microscopy, the structure of a virus-encoded machinery in its host bacterial cell membrane will be determined in different conformational states. Furthermore, pilot experiments will be carried out to express and purify individual protein components for downstream mechanistic and high-resolution structural studies. The knowledge gained will provide many further avenues for research on our quest to develop advanced bactericides and synthetic cell-based treatments, and will deepen our understanding of bacterial pathogenicity in crops and animals, including humans. Funding for this proposal will also open up a multitude of downstream opportunities for collaboration with academia and industry, and importantly will provide me with the means to launch the crucial next stage of my career as an independent investigator.

Amount: £99,386
Funder: The Wellcome Trust
Recipient: University of Exeter

Pre-conception genetic screening for conditions of uncertain or variable prognosis: social and ethical implications 05 Apr 2018

Awarded funds are for: - Developing a multi-media art installation from the research findings with the artist, Esther Fox. This installation will include an immersive soundscape capturing the complexities of genetic screening using voiced verbatim text from interviews and an interactive computer game that navigates players through life-like scenarios relevant to genomics. Many disabled people, however, face barriers when participating in cultural life, and a static exhibition does not adequately remove these. Additional funds are therefore requested to increase the inclusivity and accessibility of the installation through the use of touring and production of a film for digital dissemination. Given the centrality of the views of people with disabilities to this research, inclusivity and accessibility are of paramount importance. To achieve this we will: - Collaborate with a digital theatre and media company, STAMP, to create a touring installation. This will be exhibited for 4-5 months in 2019 at approximately five UK Science Festivals and other public venues (e.g. Cheltenham Science Festival, British Science Festival, Think Tank Birmingham). - Film the touring installation and conduct 2-3 minute ‘sound bite’ interviews with attendees. - Post the resulting film on the project website/social media accounts. Also link it to the websites of relevant charities and organisations (e.g. Genetic Alliance UK, condition-specific support groups, GeneWatchUK, US Center for Genetics and Society) - Submit the film to ‘Disorder’, the International Rare Disease Film Festival. - Evaluate the impact and reach of the installation and film through interviews, written and electronic feedback and social metrics.

Amount: £38,100
Funder: The Wellcome Trust
Recipient: University of Warwick

Building the NHS: Planning, Public Opinion and Britain’s New State Hospitals, 1945 – 1974 08 May 2018

My PhD will investigate the planning and design of new state hospitals in the years immediately preceding the NHS and during its early years. Although well recognised as a formative period for the service, there has been little rigorous research into exactly how health policy functioned in practice during this time. Impressions in both public discourse and scholarship have instead been shaped by the rhetoric of high political figures and senior civil servants who have emphasised the benign, technical, and rational aspects of decision-making. This PhD project will argue a new approach is required. Through a series of four hospital-based case studies of planning and design, it will evidence the power of local opposition and support, comparatively illustrate the persistent inequalities in healthcare, and will uncover forgotten discourses on the future of the NHS. It will restore the cultural, local, and discursive processes that really determined the progress and delay of health policy. Moreover, It will explain why both policymakers and historians alike have sub/consciously favored narratives of objectivity over a broader reading of local and regional sources. My ultimate goal in doing so is to evidence how the NHS was really built and its meaning created.

Amount: £95,368
Funder: The Wellcome Trust
Recipient: University of Warwick

Hygiene and our relationship with nature – achieving a better balance? 18 Jun 2018

Physical contact with dirt in the natural world poses a risk of infection. But does our concern to be hygienic limit our familiarity with, and therefore our respect for, the outdoor environment? Do we as a result persist with practices that threaten both our health and that of the planet? Working with Warwickshire Wildlife Trust (WkWT), based at their Brandon Nature Reserve, I will investigate how concerns about hygiene affect interaction between humans and the natural world. I will evaluate practices in this regard at Brandon, to establish how far this location can be held up as a model in terms of the ways institutions safeguard members of the public whilst having minimal impact on the environment. I will interview WkWT’s partner organizations such as schools, and report on how they minimize risks whilst promoting respect for nature. I will talk to staff and visitors at WkWT about balancing hygiene with a love of nature. Building on these conversations, I will formulate a questionnaire with which to approach the wider public. Working with WkWT’s schools team, I will devise a range of curriculum- linked workshops exploring how animals keep clean in the wild in comparison with human practice.

Amount: £12,149
Funder: The Wellcome Trust
Recipient: University of Warwick

A Healthy Interest: diets, exercise, and ideal bodies in England and Holland, 1650-1800. 08 May 2018

My thesis will analyse diet and exercise advice and practices to investigate attitudes to ‘healthy bodies’ in Dutch and English printed medical literature, physician’s casebooks, patient-physician correspondence, and recipe books between 1650 and 1800. With modern concerns around increasing obesity rates and an ever-growing body of dietary advice in both medical and popular literature, a study of diets and exercise in the past can help us understand where our current ideas and ideals concerning body and health originate. The key goals of this project are to locate the health values and practices that were being promoted at this time; to assess to what extent dietary advice and ideals reached lay society; to analyse to what extent patients followed advice and made dietary and exercise considerations part of their ‘lifestyle’; and to examine attitudes to ‘healthy’ or ‘unhealthy’ bodies and bodily ideals in late seventeenth and eighteenth-century Dutch and English society. Examining manuscript and printed sources in a geographically comparative study will provide a rich and in-depth understanding of contemporary ‘health cultures’ and bodily ideals. In so doing the thesis will analyse how far we can identify the development of a modern ‘health culture’ in this period.

Amount: £99,441
Funder: The Wellcome Trust
Recipient: University of Exeter

Puffery or Policy: E-cigarettes and the role of the media in the implementation of medical and public health advice 18 Jun 2018

My project focuses on the e-cigarette industry to explore the role of the media on public opinion. Both print press and audio-visual media strongly influence the socio-cultural values attached to addictive substances. They portray the relationship between the supplying industries and public health; frame both promotional advertising and health warnings; and finally, provide the multiple-platforms of information (and addiction) transmission. The public can be overwhelmed by this wealth and profusion of contradictory claims, undermining genuine expert recommendations. Research can help to overcome this. A chronological evaluation of textual and audio-visual media, tracing the shifting relationship and negotiations between the many stakeholders (public health, Cancer Research UK, the media, e-cigarette industry and consumers), will demonstrate the changing socio-cultural associations of e-cigarettes. Having established this background, interviews with these stakeholders will explore the advertising and health recommendations of both health policy and the e-cigarette industry across different media platforms -- exploring which advice is trusted and followed. This project creates a transferable framework and approach to build positive relationships with emerging industries promoting new products not easily categorised as ‘healthy’ or ‘unhealthy’. This research also assesses the most effective and appropriate media platforms to broadcast health advice in the future.

Amount: £7,625
Funder: The Wellcome Trust
Recipient: University of Warwick