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The Wellcome Trust


The role of autophagy in cancer cell motility 29 Nov 2016

This project will investigate the role of autophagy in cell motility taking advantage of novel prostate cancer cell lines that mimic stages of disease progression (including EMT and metastasis) available through my collaborators at NTU. In particular it will address the role of the actin nucleator JMY, a p53 co-factor that impacts of autophagosome formation, cell motility and survival in autophagy-mediated effects on cell survival and the role of actin nucleation. Specific goals during the duration of the funding: -assess autophagy levels (both basal and induced) in cancer cells lines and correlate with cell motility and invasion (also assessing cell survival and adhesion/motility events, using impedance measurements, to distinguish between effects on proliferation vs motility). -Assess impact of JMY on autophagy-mediated motility (using specific mutants to distinguish autophagosome targeted vs not, and Arp2/3-independent vs dependent actin nucleation. -Assess impact of modulating autophagy levels on cell motility (i.e., through siRNA/CRISPR-Cas9 targetting of JMY and autophagy initiator proteins and small molecule inhibitors of various stages in autophagosome formation).

Amount: £71,786
Funder: The Wellcome Trust
Recipient: Nottingham Trent University

Uncovering the Pharmacology of GPR75: Role in Pulmonary Arterial Hypertension 29 Nov 2016

Pulmonary arterial hypertension (PAH) is a devastating condition that if left untreated has an average life expectancy of less than three years from diagnosis. PAH is associated with proliferation of pulmonary artery smooth muscle cells (PASMC), which contributes to increased vascular resistance. The maintenance of the low vascular tone in the pulmonary circulation is dependent on the interaction of circulating and locally produced mediators, many of which act via G protein-coupled receptors (GPCRs). The accessibility of GPCRs on the plasma membrane, their tissue-selective distribution and role in regulating physiological functions make them excellent pharmacological targets. We used an "unbiased" approach (GPCR real-time-PCR arrays) to profile GPCR expression in PASMC isolated from control and PAH patients. Our data revealed that PAH-PASMC uniquely express an orphan GPCR (whose endogenous ligand has not yet been identified) compared to control-PASMC, namely GPR75. We aim to validate GPR75 as a novel target for PAH by uncovering its pharmacology and the functional significance and expression of receptor variants in PAH and by elucidating its physiological role in-vivo. Our hypothesis is that GPR75 is a key regulator of PASMC proliferation that characterizes PAH and is an exciting new target or genetic risk factor for the disease.

Amount: £99,881
Funder: The Wellcome Trust
Recipient: University of Aberdeen

Accessing the allodynia circuitry for persistent pain 29 Nov 2016

Chronic pain affects 30% of the population(1) and significantly reduces quality of life because treatments are ineffective(2). Allodynia or touch-evoked pain is a particularly debilitating chronic pain symptom. A significant challenge to improving pain management is that the spinal neural circuitry that mediates allodynia is poorly understood. Recent efforts to characterise this circuitry have focussed on traditional inflammatory and neuropathic preclinical pain models(3). However, these ‘classical’ models do not emulate the ‘chronicity’ of clinical pain. More recently developed ‘hyperalgesic priming’ models mimic the transition from acute to chronic pain and are therefore more suited to study the allodynia circuitry relevant for persistent pain(4, 5). Moreover, the allodynia circuitry in hyperalgesic priming models may actually be different because the underlying pathological plasticity is distinct from that identified in classical preclinical pain models(6, 7). This proposal will determine whether Fos-EGFP transgenic mice(8) can be used to gain morphological, electrophysiological and genetic ‘access’ to allodynia circuitry, in the clinically relevant persistent pain model of hyperalgesic priming. This innovative approach will generate pilot data for a larger grant application to characterise and facilitate future therapeutic targeting of allodynia circuitry.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Developing drugs as a treatment for myotonic dystrophy 02 Oct 2016

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It is a highly debilitating condition affecting more than 100,000 patients in developed countries with an average life expectancy of 58 years. DM1 is primarily a neuromuscular disorder, which also affects a range of other systems including the heart, brain, endocrine and digestive systems. Patients may also show specific patterns of psychological dysfunction and personality traits, cognitive impairment/mental retardation and excessive daytime sleepiness. All features show an obvious deterioration with time and difficulty swallowing and sucking food into the lungs in the later stages of the disease contribute towards chest infections and represent a major cause of morbidity and mortality. There is no treatment for DM1. DM1 is caused by a repeat expansion mutation in the 3' untranslated region of the DMPK gene. Unaffected people have 5 to 30 copies of this sequence whereas patients may have hundreds or sometimes thousands of copies. When expressed the DMPK expansion transcripts remain in the nucleus where they form distinct spots or foci. Professors Chris Hayes and David Brook at the University of Nottingham developed an assay to screen for compounds that might provide a treatment for DM1. They identified small molecules that target a novel protein and destroy the spots in DM1 cells, thereby leading to a significant reduction in the faulty RNA and other molecular features of the disorder. Their drug discovery approach, in collaboration with Argenta, a Charles River company, is based on targeting this novel protein, by refining the chemical starting points to make them more selective and more suitable for oral administration to patients. The multisystem nature of DM1 provides particular challenges but Professors Hayes and Brook anticipate that a successful drug would target most/all features of the disease

Amount: £356,400
Funder: The Wellcome Trust
Recipient: University of Nottingham

Inhibitors of Lysyl Oxidase for the Prevention and Treatment of Invasive and Metastatic Cancer 02 Oct 2016

The enzyme lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix. LOX also plays a role in stimulating the metastatic spread of cancer through the body. Its expression is increased in hypoxic cancers and is correlated with tumour metastasis and decreased patient survival. In model systems its inhibition significantly decreases cancer metastasis and increases survival. Since metastasis is responsible for over 90 per cent of cancer deaths these data validate LOX as an important therapeutic target in cancer. Professor Caroline Springer and Professor Richard Marais from the Institute of Cancer Research have been awarded Seeding Drug Discovery funding to develop drugs that target LOX. They are applying a medicinal chemistry drug discovery approach underpinned by a strong programme in LOX biology with the aim of producing orally available, small molecular weight drugs that inhibit LOX activity for cancer treatment.

Amount: £402,800
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Discovery and development of novel small molecule inhibitors of the human Hyperpolarization activated Cyclic Nucleotide-gated 2 (HCN2) ion channel for the treatment of inflammatory and neuropathic pain 02 Oct 2016

Treatments for inflammatory pain (IP) and neuropathic pain (NP) are frequently ineffective and have many side effects. Scientists in Professor Peter McNaughton's laboratory at the University of Cambridge have discovered that both IP and NP are abolished in mice when an ion channel is genetically deleted. This suggests that drugs blocking this ion channel will have value as novel analgesics. IP is associated with injury, infection or chronic conditions such as arthritis; and NP is caused by nerve damage in conditions such as post-herpetic neuralgia and diabetic neuropathy. Both IP and NP can impose major limitations on lifestyle and working patterns and currently available treatments have major drawbacks. For example, non-steroidal anti-inflammatories cause gastric and renal damage; and opioids cause constipation and problems with tolerance and addiction. The team aims to develop selective ion channel blockers, which avoid those that play essential roles in the heart and brain, and test them in animal models of IP and NP. In separate parallel studies they will use a known non-selective blocker to carry out proof-of-principle studies in human NP.

Amount: £336,980
Funder: The Wellcome Trust
Recipient: King's College London

The Science of Rabies Elimination 11 Jul 2017

Rabies is a horrific, but vaccine-preventable disease that kills thousands of people every year in low-income countries. International agencies now advocate investment in rabies control and have set a 2030 target for global elimination. With regional programmes underway, the major research questions are now how to optimize rollout and impact, addressing challenges as elimination is approached. My fellowship aims to address these questions through synergistic research embedded within large-scale rabies control programmes around the world.   Through a large-scale vaccination intervention in Tanzania I will test the hypothesis that rabies circulates at low incidence with spatial correlations in transmission curtailing outbreaks through localized susceptible depletion, and permitting co-circulation of genetically divergent lineages. I will pilot surveillance approaches to increase case detection, improve patient care, track the spread of infection and inform elimination programmes. The resulting data will be used to formulate and parametrize models to investigate strategies to rapidly control rabies, minimize incursion risks, and maintain disease freedom.   A global network of scientists, policy-makers, and practitioners provides an enabling environment for my intervention-based research across intercontinental settings. Findings will therefore translate directly into policy at the highest level, delivering impact through timely transferrable insights to guide elimination efforts.

Amount: £2,290,232
Funder: The Wellcome Trust
Recipient: University of Glasgow

Sexy glia: developmental plasticity during glia-derived neurogenesis 11 Jul 2017

The overall goal of this proposal is to elucidate the cellular and molecular mechanisms that regulate natural glia-to-neuron cell-fate switches. Stably differentiated cells can sometimes display a remarkable degree of plasticity and switch fates to another differentiated cell type, in a process termed transdifferentiation. In the vertebrate nervous system, radial glia act as neural progenitors during embryogenesis. Suprisingly, stably differentiated glia can also act as neural progenitors during adult neurogenesis. We have recently discovered two cases in which stably differentiated glial cells undergo a glia-to-neuron cell-fate switch during sexual maturation in the nervous system of C. elegans, allowing us to study these events at the single-cell level in a genetically tractable system. We will combine classic genetic approaches with state-of-the-art molecular and next-generation sequencing approaches to characterise the molecular and epigenetic changes that occur during natural glia-to-neuron transdifferentiation. We will elucidate the role of cell division in this process, identify novel molecular regulators and determine the reprogramming abilities of the factors we identify. Unleashing the neurogenic potential of glia offers tremendous therapeutic possibilities.

Amount: £1,453,931
Funder: The Wellcome Trust
Recipient: University College London

Investigating the physiological DNA replication initiation reaction 30 Nov 2016

In all cells chromosome replication requires key initiator proteins to unwind the DNA at specific sites termed origins. Despite the fundamental importance of DNA replication initiation, crucial aspects of the process remain poorly understood. My vision is to identify all essential features of both the bacterial replication origin and DNA replication initiation proteins in vivo. This comprehensive reverse genetic analysis will guide biochemical investigations into the activities associated with deleterious mutations, thereby revealing the interactions and steps necessary for the physiological initiation reaction. Towards this goal I have created a bespoke tool: an inducible heterologous replication initiation system that allows construction and characterization of mutations within endogenous replication initiation factors. This methodology, combined with assays we developed to analyze DNA replication initiation in vitro, led us to identify a new essential bacterial replication origin element (Richardson et al. Nature 2016). We will build upon this successful approach and go on to develop more sophisticated heterologous replication systems, opening the door to studying all aspects of chromosome replication. Importantly, the bacterial DNA replication machinery is an underexploited drug target. Knowledge of bacterial DNA replication resulting from this work will provide a guide for disrupting this process in pathogenic species.

Amount: £1,535,316
Funder: The Wellcome Trust
Recipient: Newcastle University

Embryo architecture, potency and tissue interactions during mouse and human development 11 Jul 2017

Mammalian embryogenesis entails close partnership between embryonic and extra-embryonic tissues to regulate changes in embryo architecture and developmental potency. We aim for an integrated view of how these events progress hand in hand during key stages of mouse and human embryogenesis. The first architectural changes of the embryo are polarisation and compaction that trigger the separation of embryonic and extra-embryonic lineages. Yet their own trigger remains unknown. We will dissect potential triggering pathways and through genetic manipulations determine their importance for cell fate. Embryo remodelling at implantation is intimately associated with pluripotent-state transitions. We will harness our novel techniques for embryo culture throughout implantation to uncover mechanisms behind these events in relation to signalling partnerships between embryonic and extra-embryonic tissues. By arranging partnership between embryonic and extra-embryonic stem cells in 3D-culture we have recapitulated embryo-like morphogenesis and spatio-temporal gene-expression. We will characterise tissue interactions in such stem cell-derived embryos to understand principles of self-organisation. Our work established an unprecedented opportunity to study human early post-implantation embryogenesis in-vitro. We will build the first morphological and transcriptional atlas of human development beyond implantation. This will bring understanding of normal development and shed light upon why many pregnancies fail at early stages.

Amount: £2,135,983
Funder: The Wellcome Trust
Recipient: University of Cambridge

Structure and mechanism of nucleic acid-processing machines in viral biogenesis 05 Apr 2017

The research will focus on analysing the structure and mechanism of nucleic acid machines involved in viral biogenesis. Although the main emphasis is on using structural approaches such as X-ray crystallography and Cryo-EM; we will also use complementary biophysical techniques including surface plasmon resonance, fluorescence-based activity/binding assays, analytical ultracentrifugation and SEC-MALLS, to define composition and stoichiometry of protein-nucleic acid complexes, in addition to the affinity of the interaction. Key goals: To continue investigation into the mechanism of dsDNA packaging motors present in tailed bacteriophages and the closely related human herpes viruses. To obtain high-resolution asymmetric cryo-EM reconstructions of an active motor assembled from components derived from a themostable bacteriophage. To understand the structure-function relationship in FtsK-like DNA packaging motors present in another large class of dsDNA viruses comprising bacterial tectiviruses and eukaryotic poxviruses. To investigate the mechanism of RNA unwinding by 2C helicases present in enteroviruses (such as poliovirus) and to define the RNA-binding surface of the Zika Virus NS3 helicase. To perform pilot studies on exploiting this information for identifying lead compounds for the development of antivirals.

Amount: £1,806,188
Funder: The Wellcome Trust
Recipient: University of York

Bone Morphogenetic Protein signalling and stromal-epithelial interaction in intestinal inflammation and carcinogenesis. 05 Apr 2017

The intestinal mucosa is a complex ecosystem and the epithelium has a dynamic relationship with underlying stroma. Key aspects of intestinal homeostasis and disease states, including inflammatory bowel disease and cancer are characterized by the interdependence of the epithelial and stromal compartments. Inter-compartmental cell-signalling pathways regulate intestinal epithelial cell fate determination in homeostasis, and transient perturbation of these networks is required in the physiological response to inflammation and injury. This promotes epithelial stem cell behaviour, cell proliferation and migration as part of a wound healing response. However, failure of restoration of homeostatic control in chronic inflammation, or pathological disruption of signalling can result in neoplasia initiation and progression. In resultant tumours, optimally selected somatic mutation spectra differ and reflect these variable influences on lesion pathogenesis. This proposal will explore these concepts using disruption in Bone Morphogenetic Protein signalling and it's pleiotrophic antagonist Gremlin1, as exemplars of the paradigm. Specific goals include: 1. Identifying stromal cell populations expressing Grem1 in intestinal regeneration and tumour desmoplasia. 2. Assess the functional role of BMP disruption in these conditions. 3. Using mouse models to test therapeutic manipulation of BMP signalling. 4. Using somatic mutation analysis to generate molecular biomarkers of Grem1 initiated tumourigenesis.

Amount: £1,792,405
Funder: The Wellcome Trust
Recipient: University of Oxford

Integrating the management of depression into routine HIV care in Uganda (the HIV+D trial) 30 Nov 2016

This project aims to demonstrate the feasibility and effectiveness of a mental health integration model in general adult HIV care services to bridge the treatment gap for mental disorders in HIV/AIDS that currently exists in most of sub-Saharan Africa. The proposed model will be based on the MANAS intervention which is stepped care collaborative care delivery model coordinated by a lay health worker for depressive and anxiety disorders in public primary health care attenders in India. This study will have the following objectives: i) to adapt the MANAS collaborative stepped care intervention to the general HIV care situation of Uganda, including the local adapatation of the Health Activity Program (HAP) therapy for depression; ii) to undertake a cluster randomised trial to evaluate the effectiveness on depressive disorders (DD) and functional outcomes and cost-effectiveness of the intervention in routine HIV care in Uganda. This study will be undertaken among persons living with HIV attending public health care facilities in three districts of Uganda. The planned intervention will involve screening for DD, psychoeducation, administration of HAP and use of antidepressant medication to be delivered by lay health workers, the HIV care team with support from specialist mental health workers.

Amount: £2,021,099
Funder: The Wellcome Trust
Recipient: MRC/UVRI Uganda Research Unit on AIDS

Imaging Focal Epilepsy in Children: A Developmental Perspective 31 May 2017

Focal cortical dysplasias are common causes of treatment-resistant epilepsy in childhood, but are persistently difficult to detect on clinical magnetic resonance imaging (MRI) scans by routine visual inspection. This is especially true in children, where pathology may be masked by the dynamically changing background of the developing brain. My fellowship will investigate focal epilepsy in the context of the developing human brain. I will build analytical tools from clinical MRI data to better detect subtle MRI lesions and, using quantitative MRI (qMRI), translate these tools so they can be applied across clinical sites and in other neurodevelopmental and neurological disorders. I propose to build a continuous time-space model of brain development using large population MRI data from typically developing children. Using this model, I will test the specificity of abnormality maps in individual patients to confirmed epileptic pathology in a training- and test-dataset from two large epilepsy neurosurgery programmes. To generalise this model to standard clinical sequences, I will collect qMRI and synthesise scanner-independent MR images to tailor this growth model to any local protocol. Finally, I will extend these structural findings to identify networks associated with focal epilepsies, and investigate whether they can predict a successful outcome from surgery.

Amount: £995,096
Funder: The Wellcome Trust
Recipient: King's College London

Super-resolving the physical mechanisms of bacterial cell division 31 May 2017

I aim to reveal the elusive basic principles of bacterial cell division by super-resolution microscopy. This is the next step in my long term vision to discover fundamental principles of how protein nanomachines spatially organize cells. The bacterial cell division machinery is a crucial cellular module essential for bacterial survival, and a mechanistic understanding of division is essential to understanding mode of action of cell-division-targeting antibiotics. Cell division is also a fascinating puzzle: bacteria and animal cells both use a cytoskeleton to constrict the cell; but how do bacteria, unlike animal cells, manage to do so without using any motor proteins? The mechanistic principles of bacterial cell division have escaped elucidation for decades because the cell division machinery is organized on a scale below the diffraction limit of conventional microscopy. I will overcome this problem by pushing the limits of super-resolution microscopy to reveal the organization and motion of the Bacillus subtilis cell division machinery at unprecedented resolution. This will reveal the physical mechanisms of cell division by answering three critical questions: How is the bacterial cell division machinery organized? How does it generate constrictive force? How is force generation coordinated with remodelling of the bacterial cell wall?

Amount: £1,013,145
Funder: The Wellcome Trust
Recipient: Newcastle University

Improving self-awareness: Manipulating the neural substrates of self-belief 31 May 2017

Beliefs about our skills and abilities (known as "self-beliefs") may become divorced from reality, particularly in psychiatric and neurological disorders. For instance, someone with depression may think they are unable to succeed in new pursuits, making them unlikely to try in the first place. My goal is to identify core brain processes supporting self-beliefs, and in turn leverage this knowledge to develop interventions for restoring aberrant self-belief. I will focus on a network of brain regions in medial and lateral prefrontal cortex that is theorized to support estimates of self-ability. I will address three interlocking questions: 1) How are self-beliefs constructed? 2) Which factors permit the modification of self-belief? 3) How are self-beliefs used in the control of future behaviour? I will conduct fMRI and MEG experiments using novel decision paradigms to dissect elements of self-belief computation such as prior experience and task difficulty, and reveal how mental health is linked to these computations through large-scale online data collection. This work will inform behavioural and neurofeedback interventions to modify self-belief. The overarching goal of my research agenda is to produce a comprehensive, mechanistic account of self-belief construction, thereby informing efforts to restore appropriate self-awareness in disorders of mental health.

Amount: £844,232
Funder: The Wellcome Trust
Recipient: University College London

Regulation of nuclear envelope function and links with disease 22 Feb 2017

The nuclear envelope (NE) lies at the interface between the nucleus and the cytoskeleton. It forms a complex structure controlling cell compartmentalization and regulates many processes including nucleo-cytoplasmic transport of proteins and RNA, chromatin organization, DNA replication and DNA repair. Hence, defects in NE integrity and nuclear architecture cause drastic changes in cell homeostasis and are associated with a broad range of diseases including cancer, premature ageing syndromes, neurodegenerative diseases or muscular dystrophies, but also with physiological ageing. One of the main challenges is to understand how NE defects lead to so many types of diseases. Previous theories include changes in gene expression and mechanical weakness. My previous work has shown that subcellular processes including microtubule or chromatin organization can modulate NE function, and has identified the acetyltransferase NAT10 as a key regulatory node for control of nuclear architecture. My goal is to now investigate how NAT10 and other factors regulate the NE. I will thereby gain new understanding of how of nuclear architecture is orchestrated and how this is disrupted in age-related diseases including HGPS. This research will not only contribute to our fundamental understanding of nuclear architecture but will also potentially identify new therapeutic strategies for NE-associated syndromes.

Amount: £1,084,517
Funder: The Wellcome Trust
Recipient: University of Cambridge

Determining the mechanisms regulating immune-directed clearance of senescent cells to promote healthy ageing 22 Feb 2017

The number of people over the age of 65 is predicted to double by 2060, accompanied by an increase in chronic diseases, which already consume up to 80% of healthcare costs. Developing therapies for chronic ageing diseases is, therefore, an urgent priority. A key driver of ageing diseases is telomere dysfunction and consequent cell senescence. Genetic ablation of senescent cells ameliorates diseases of ageing in mice, highlighting senescence as a promising therapeutic target. The immune system clears senescent cells, but with ageing, senescent cells accumulate causing disease. The mechanisms regulating senescent cell clearance in telomere-dependent ageing in vivo are unknown. I will test the hypothesis that senescent cells are not cleared with ageing due to telomerase-dependent dysfunction of the immune system. I will use the premature ageing telomerase mutant zebrafish I developed, which age in a telomere- dependent manner, and are exceptionally amenable for imaging and genetic manipulation. I will determine which leukocytes clear senescent cells in aged tissues in vivo, identify the key mechanisms involved and determine how these change with ageing. I will then test whether manipulation of these targets is sufficient to prevent or delay tissue degeneration and frailty in old zebrafish.

Amount: £1,143,611
Funder: The Wellcome Trust
Recipient: University of Sheffield

Imaging and activation of glymphatic clearance: a novel strategy for Alzheimer’s Disease 26 Oct 2016

There is a critical need for early and accurate biomarkers of the pre-symptomatic phase of Alzheimer's disease (AD), to maximise the efficacy of emerging therapies. Recent evidence implicates cerebral glymphatic exchange as a key mechanism in early AD pathogenesis [Figure 1] [1-4]. I will develop the first non-invasive method for the quantitative assessment of glymphatic clearance, using MRI. These novel methods will be carefully validated by comparison with the invasive measures [5], that I have previously established, in normal, aged and AQP4 null mice. I will apply these novel techniques longitudinally to mouse models of ageing and AD (amyloid and tau) to investigate impairment of glymphatic clearance relative to more established markers of AD pathogenesis such as structural imaging, perfusion and histological assessment of plaque/tangle burden. As such, these data will be the first to elucidate the chronology of abnormal glymphatic clearance in AD pathogenesis. Finally, I will combine these methods with targeted optogenetics to assess the interaction of vessel tone and vasomotion to rates of glymphatic clearance in order to characterise the underlying mechanisms that drive CSF-ISF exchange.

Amount: £780,158
Funder: The Wellcome Trust
Recipient: University College London

Investigating the functional basis of shared genetic etiology across autoimmune diseases 26 Oct 2016

Autoimmune diseases are a diverse set of conditions afflicting ~10% of the population worldwide, they pose a substantial personal and socioeconomic burden, and they have no cure. Currently prescribed treatments have variable efficacies and can be associated with severe side effects such as malignancies and even fatal opportunistic infections. Designing improved therapeutic strategies requires a better understanding of the pathways that drive these conditions to achieve an optimal modulation of the immune system. Investigating the biological consequences of disease-associated genetic variants provides an avenue for delineating critical pathophysiological mechanisms. However, for each of these conditions, tens to >100 different loci have been found to influence disease risk. Therefore, prioritization is required, and the approach taken in this proposal is to focus on genetic variation shared across multiple autoimmune diseases, including a polymorphism in the tyrosine kinase 2 (TYK2) gene that protects against no fewer than 11 such conditions. The key goals of this research are to (i) investigate the molecular basis of shared genetic risk across autoimmune diseases; (ii) elucidate the downstream signatures and impact of shared genetic risk to help define key disease pathways; and (iii) investigate how key disease pathways can be fine-tuned for maximal benefit.

Amount: £1,009,370
Funder: The Wellcome Trust
Recipient: University of Oxford