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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

Exploring endosomal signalling of G protein coupled receptors (GPCRs) using luciferase complementation and luminosensing optogenetics 31 May 2018

Recently G protein coupled receptors (GPCRs) have been shown to signal from intracellular compartments such as endosomes, as well as the cell surface. There is increasing evidence that some synthetic drugs can activate such intracellular located GPCRs directly, but the functional consequences of this activation have been difficult to isolate. This project will study endosomal signalling from engineered optogenetic receptors (OptoXRs), activated by light and coupled to the Gq pathway linked to calcium mobilisation. I will deliver the light stimulus to OptoXR using bioluminescence from a luciferase enzyme, in a local manner to receptors either at the cell surface or within endosomes. This will be achieved using a complementation system, in which luciferase fragments are tagged to the OptoXR and cell surface or early endosomal markers respectively. Active luciferase will therefore only be reconstituted to deliver the light when the OptoXR is present in the same location as the expressed marker. I will then be able to compare the effect of adding the substrate on OptoXR calcium responses in which case, to determine whether calcium signals are produced from receptors in different locations. This will be backed up by confocal and luminescence microscopy to identify reeptor and luciferase locations.

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

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

DNA-clustering in yeast 31 May 2018

We propose to describe mathematically the processes by which telomeres form clusters in the nuclei of yeast cells. It is thought that this is due to the presence of proteins which bind to the telomeres. We wish to investigate the processes which determine cluster size through: 1. forming a mathematical model of the attachment processes through which proteins bind to telomeres. This may involve a site exclusion process, whereby the protein binding rate slows due to the declining number of vacant protein binding sites as the telomere `fills up'; 2. constructing a mathematical model of the aggregation of telomere-protein complexes into clusters, and determine which rate parameters are key to controlling cluster size; 3. investigating the rate of equilibration of these processes. The models we construct will have the form of systems of coupled ordinary differential equations. Through a judicious choice of rate constants, explicit equilibrium solutions will be obtainable, allowing available data to be fitted. Numerical simulations of the process will also be performed, to verify that the equilibrium solutions are accessible within biologically realistic time periods.

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

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

Synthesis, characterisation and biological evaluation of a novel library of iminosugar compounds as inhibitors of Galactofuranosyl Transferase 2 inhibitors in Mycobacterium Tuberculosis 30 Sep 2018

The increasing prevalence of antimicrobial resistance (AMR) represents one of the greatest existential to humanity. Of particular concern is the emergence of multi-drug and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB) infections which significantly diminish the treatment prospects for patients. This means that there is a distinct need for novel anti-TB drugs with unique targets which will allow them to circumvent the resistance to conventional drugs. One such target is the Galactofuranosyl Transferase 2 (GalfT2) enzyme. This enzyme plays a key role in the generation of the alternating beta-1,5 and beta-1,6 furanose linkages which make up a significant portion of TB’s complex cell wall. Knock-out studies have shown that this enzyme is vital to TB viability making it an attractive drug target. Previous work in the Thomas group identified iminosugars as a weak inhibitor of GalfT2. The aim of this project is to synthesise a library of these iminosugar compounds and explore their efficacy as GalfT2 inhibitors using both whole-cell and enzyme assays. Structural elaboration will be performed, principally driven by in silico drug design which will attempt to improve the inhibitory properties. The hope of the project is to identify novel iminosugar compounds which can act as effective anti-TB compounds.

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

Mathematical modelling of inflammation 31 May 2018

The proposed research seeks to build on existing mechanistic mathematical models for the inflammatory response by generalising them to structured-population frameworks able to capture, in particular, a continuum of macrophage states, motivated by a desire to shed light on the processes that regulate whether resolution or dysregulation of inflammation occurs. The level of the modelling assumptions and analysis will reflect what can realistically be achieved over the course of a Vacation Scholarship. Interactions of macrophages and neutrophils with bacterial biofilms will provide a concrete focus for the application of the general models, arising from discussions with (and enabling guidance from) microbiologists within the University. The key goals are: (i) Construction and extensive numerical simulation of a structured-population model that encompasses macrophage and neutrophil populations and builds directly on extant ordinary-differential-equation formulations. (ii) Generalisation of the model to include spatial effects, allowing the simulation of an idealised model for the interaction of inflammatory cells with a heterogeneous biofilm. (iii) Interpretation of results, providing the Scholar with experience of systems-biology research as applied to topics of direct relevance to healthcare.

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

Axonal miRNAs in the development and function of neuron connectivity: intra-axon and inter-neuronal actions 04 Dec 2017

Brain function depends on the correct formation, maintenance and constant changes of neuronal circuits. Among the multiple signaling pathways regulating these processes, microRNAs have emerged as crucial regulators of gene expression able to control the development and remodeling of neural connections. However, there is still a very limited understanding of their role in axon biology and inter-neuronal communication. Our central hypothesis is that specific miRNAs can be transported to the axon and regulate the development and function of neuronal connectivity via the control of local axonal translation (cis-action) and inter-neuronal (trans-action) mechanisms mediated by release of extracellular vesicles/exosomes. We will test this using a multidisciplinary approach with innovative cellular and molecular techniques based around compartmentalised microfluidic devices for the culture of mouse primary cortical neurons. The characterisation of axonal miRNAs and their capacity for intra- and inter- cellular action could transform our current understanding of the role of miRNAs in the development and function of neuronal networks. The impact of these findings will be many, both at the level of basic neuron connectivity, and in the understanding of neurodegenerative disease, where disruption of axonal projections and neuronal circuits has been intrinsically linked to progressive functional decline.

Amount: £99,730
Funder: The Wellcome Trust
Recipient: University of Nottingham

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 Awards 2017/18 30 Sep 2018

Not available

Amount: £14,351
Funder: The Wellcome Trust
Recipient: University of Nottingham

Open Access Award 2017/18 30 Sep 2018

Not available

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

Imaging Flow Cytometry 05 Jul 2018

We seek funding for an ImageStream X Mark II Imaging Flow Cytometer to be hosted by the University of Nottingham (UoN) Flow Cytometry Facility. This exciting technology combines the speed, statistical robustness and multi-parametric data of conventional flow cytometry with the detailed localisation information of microscopy. The machine has been specified following a trial demonstration and in consultation with our extensive user group and co-applicants. It includes five lasers, high magnification, extended depth of field and automated sampler options that would make it one of the most capable machines in its class in the UK. An imaging cytometer would significantly enhance research capability by offering unique high number and high content experiments. Novel applications include the ability to detect, enumerate and characterise rare cells; the ability to dissect cell signalling events through precise measurements of nuclear translocation events or co-localisation; the study of extracellular vesicles in both eukaryotic and prokaryotic systems; precise quantification of drug delivery/internalisation; and the study of cell death mechanisms. We have established mechanisms for access, charging and an extensive client list that have indicated keen interest in this technology, and have secured a 30% financial contribution from the University demonstrating the strategic importance of this equipment.

Amount: £335,298
Funder: The Wellcome Trust
Recipient: University of Nottingham