NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Cancer  Metabolism
Funder: The Francis Crick Institute

Abstract: The overall aim of my lab is to elucidate the fundamental principles that govern the spatiotemporal regulation of metabolism in mammalian organisms. The ultimate goal is to understand how these mechanisms are perturbed in disease and use this knowledge to design novel pharmacological approaches for cancer therapy and prevention. Towards these goals, research in my lab focuses on three complementary approaches:  (1) We use in vivo metabolic tracer studies and metabolic imaging in mouse models of liver regeneration and disease to investigate how metabolic communication between organs is altered during tumorigenesis to support cancer growth. These studies indicate that tumours engage in an intricate metabolic cross-talk between various organs to re-programme metabolism throughout the mammalian body which leads to the use of nutrients not normally implicated in normal organ function.   (2) We develop physiologically relevant tissue culture models of cancer that we use for metabolic tracer studies to understand the role of subcellular compartmentalisation in metabolic regulation. This work, complemented by biochemical reconstitution of metabolic pathways in vitro has uncovered new insights into the mechanisms by which metabolic pathways separated in different cellular niches are coordinated and point to a critical role for these mechanisms in supporting cancer cell survival in response to stress. (3) We use computational modelling to predict the allosteric pathways through which metabolites influence protein function and use this information to engineer proteins with altered allosteric properties that can be controlled in a reversible manner through optogenetic methods. As allostery is crucial for the rapid adaptation of metabolic pathways to environmental cues, our studies provide a framework for predicting and designing novel allosteric modulators to interfere with the pathways discovered through directions 1 and 2 in cancer. Overall, since its foundation, our research programme has provided novel insights into less understood aspects of metabolic regulation thereby informing the rational targeting of metabolic pathways that contribute to tumorigenesis. We have also developed a series of mouse models and computational methods that allowed us to investigate regulation mechanisms in glucose metabolism but are broadly applicable to other metabolic pathways.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Cancer Research Technology (CRT) Discovery Labs
Funder: Cancer Research UK

Abstract: CRUK Therapeutic Discovery Laboratories (CRUK-TDL) is the in-house CRUK drug discovery unit with a principal focus on establishing and prosecuting biologically-themed multi-project alliances with industry. Based at the Babraham Research Campus, Cambridge,


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Cancer Research UK City of London Centre
Funder: Cancer Research UK

Abstract: The ‘Cancer Research UK City of London Centre’ is a powerful collaborative effort, bringing together over 350 cancer researchers from across UCL, QMUL, KCL and The Francis Crick Institute, to form a centre of excellence in cancer biotherapeutics. By uniting our multidisciplinary academic and clinical expertise across the partnership, our aim is to not only significantly impact on the development of biotherapeutics for the treatment of cancer, but revolutionise the way cancer research is conducted in London.     Biotherapies delivered as part of a multimodal/combinatorial approach have the potential to dramatically change cancer therapy and management. The Centre will develop innovative biological therapies and diagnostics/stratification strategies to develop novel, potent and selective therapeutic combination approaches.    Our platform-based, cross-disciplinary approach will nucleate cancer research activity in biotherapeutics and cancers of unmet need in our Centres and hospitals, and provide a clinical and translational conduit for Crick cancer discovery science. By uniting the population bases across the partnership, our network gives access to important patient cohorts and a referral population of over ten million, which enables excellent academic and commercially-led experimental medicine and rapid clinical uptake of novel tools and approaches.     Together the CRUK City of London Centre will foster a unified strategic oncology agenda, feeding directly into the development and deployment of biological therapies as well as allied fields including cancer prevention, evolution/resistance, imaging, and population studies.


Research Activity Codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.1 PHARMACEUTICALS;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health Categories: CANCER AND NEOPLASMS
Award Title: Capturing the spatiotemporal diversity of cellular and molecular mechanisms in ALS
Funder: Medical Research Council

Abstract: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive selective degeneration of motor neurons (MNs). We desperately need to understand disease mechanisms to guide effective therapy. The hallmark of ALS (>97% of cases) is a nuclear-to-cytoplasmic mislocalization of an RNA binding protein (TDP43). This implicates two possible disease mechanisms: i) cytoplasmic gain-of-function or ii) nuclear loss of TDP43 function. By developing robust directed differentiation paradigms from hiPSCs, we have identified: i) TDP43 nuclear displacement is a primary event in MNs; ii) aberrant intron retention (IR) is the earliest detectable event in MNs; iii) ALS astrocytes (ACs) lose neuroprotective capacity through impaired EphB1-EphrinB1 JAK-STAT signalling and iv) ageing affects ACs > neurons, shifting their regional identity away from areas of primary neurodegeneration. I now propose to: 1) examine regulation and consequences of aberrant IR in MNs; 2) investigate neuronal-subtype vulnerability by comparing MNs to relatively unaffected dorsal spinal interneurons; 3) elucidate how AC regional identity and reactive status influence their established role in ALS and 4) determine how cellular ageing of MNs and ACs contributes to manifestation of ALS. Triangulating molecular mechanisms, cell-type specific contributions and the impact of cellular ageing will allow us to 'zero' in on salient disease mechanisms.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Care, infrastructures and antiblackness: the making of biomedicine in a Sierra Leonean hospital
Funder: Wellcome Trust

Abstract: The research project offers an in-depth analysis of the conflation between biomedical practice, care and antiblackness in the colonial wake. Using historical, geographic and ethnographic methods, it examines how the history of enslavement and colonialism is entangled with notions and practices of Western biomedical care and the spatial organisation of a postcolonial hospital. As a location for this study I have chosen Connaught Hospital in Freetown, Sierra Leone. Situated on Freetown's Northern coast between White Man's Bay and Susan's Bay, this was both the setting for mandatory quarantines for liberated slaves and the site of the British-built Colonial Hospital. Working with Sierra Leonean healthcare staff, I will examine the hold this violent past has on Sierra Leonean conceptions of care and trust in biomedicine. This allows me to 1) explore how biomedicine's conflation with antiblackness shapes biomedical encounters in postcolonial Sierra Leone and 2) examine how biomedical spaces and infrastructures perpetuate feelings of distrust and exclude other forms of care. In doing so I will 1) challenge the traditional geographical remit of Black Studies, 2) study how antiblackness weaves its way through medicine and care and 3) give Fanon's analyses of colonialism, racism and biomedicine a contemporary & geographic dimension.

Lay Abstract: Background: Medicine and medical racism played an important role in the British colonisation of Sierra Leone and were integral to its administration. One site in particular bore witness to the uses of medicine by colonial officers to administer ideas around racial difference and white superiority. This site, subsequently used to quarantine liberated slaves and build a colonial hospital, is still home to one of Freetown's main hospitals. Approach: A Black Studies framework allows me to research what impact antiblack histories ingrained in this site have on the hospital's contemporary infrastructures and care practices. In doing so I foreground the persistence of antiblackness, its non-linearity and simultaneous intangibility to challenge traditional structural ways of studying health inequalities. Expected impact: The project furthers existing analyses of care, colonialism and African distrust in biomedicine, the sites associated with it and practitioners thereof, and reveals new findings on the relation between racism and medicine.

Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Cell Biology of Infection
Funder: The Francis Crick Institute

Abstract: Maintenance of appropriate intracellular electrochemical gradients is a fundamental characteristic of cells. This is frequently perturbed by invasive pathogens. Secretory and endocytic compartments are characterised by a moderately acidic and compartment specific pH. The maintenance of the pH of these compartments is important for appropriate posttranslational processing and protein and lipid sorting. We have recently shown that the M2 proton channel of influenza A virus, ionophores and other drugs that raise the pH of vesicles cause accumulation of the autophagy protein LC3 at intracellular membranes. LC3 is commonly used as a marker for autophagy, a catabolic pathway to recycle nutrients during starvation and to degrade large aggregates, damaged organelles and intracellular pathogens. A hallmark of autophagy is the formation of double membrane vesicles called autophagosomes. LC3 becomes covalently associated with phosphatidylethanolamine in both membrane layers of the autophagosome. However, pathways that result in association of lipidated LC3 with single membrane vesicles have also been described, highlighting that LC3 punctae do not always represent autophagosomes.  We suggest that IAV-induced LC3-positive intracellular vesicles are not double-membrane autophagosomes, but a highly dynamic single-membrane compartment that exhibits fusion–fission behaviour. Recruitment of the enzyme complex responsible for LC3-lipidation - ATG5-ATG12/ATG16L1- in IAV-induced LC3-lipidation critically depends on the C-terminal WD40 domain of ATG16L1. This domain is dispensable for starvation-induced autophagy. The requirement of this domain for LC3-lipidation in response to the M2 proton channel is shared by ionophores and other drugs that raise the pH of vesicles as well as LC3-assisted phagocytosis. IAV-induced LC3-lipidation therefore differs from canonical autophagy as it targets single membrane vesicles and relies on a distinct ATG16L1 recruitment pathway. To identify genes involved in this process, we have designed sophisticated whole genome CRISPR knock-out screens. These confirm that the LC3 lipidation machinery is required, but not the upstream components of canonical autophagy.  Many pathogens cause subtle damage to endomembrane compartments, thereby inhibiting their acidification. We propose that LC3 targeting in this context represents a mechanism for detecting a ‘danger’ signal of erroneously neutral, e.g. possessing a higher pH than appropriate, vesicles.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Cell biology of host-pathogen interactions in tuberculosis
Funder: The Francis Crick Institute

Abstract: To live within eukaryotic cells, M. tuberculosis developed through evolution an impressive set of molecular tools. Many clinical manifestations and problems during treatment of tuberculosis are a direct consequence of a population of intracellular bacilli. Although in vitro and in vivo studies have shed light into some aspects of tuberculosis pathogenesis, we still do not completely understand how M. tuberculosis manages to survive within eukaryotic cells. We believe that a detailed understanding of host-mycobacteria interactions will provide insights not only into the mechanisms usurped by mycobacteria to survive, but also into basic aspects of cellular functions and in the innate immune system. Research in our group focuses on the mechanisms whereby M. tuberculosis arrests phagosome maturation and avoids killing by macrophages and non-phagocytic cells. Towards this goal, we study the intracellular transport of M. tuberculosis in macrophages, epithelial and endothelial cells. We have identified novel factors involved in vesicular trafficking and protein sorting, particularly phago-lysosome fusion, during infection. These proteins are promising candidates for being involved in the lysosomal-mediated killing of M. tuberculosis, as well as in the molecular events linking innate and adaptive immune responses. We are currently characterizing the role played by these proteins during the development of innate and adaptive immune responses.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Cell therapy for Huntington's disease: addressing critical knowledge gaps
Funder: Medical Research Council

Abstract: Cell therapy provides a strategy for treating diseases in which predominant loss of a specific neural cell type is responsible for a substantial element of the functional decline.  Huntington's disease (HD) is a devastating, incurable condition, and is a good model for testing cell therapy as loss of striatal medium spiny neurons (MSNs) is a prominent and early feature, and strongly related to functional decline. We have worked on cell therapy for HD for many years. We have developed considerable preclinical knowledge and have started to prepare for clinical translation.  The most robust preclinical knowledge is based on rodent foetal allografts, although human foetal cells have shown proof of concept improvements in HD patients. Foetal cells are 'properly' specified through normal development and so provide essential benchmarking, but widespread clinical application will require MSN to be derived from renewable donor sources, such as human embryonic stem cells (hESC-MSNs). Here we address critical questions of hESC-MSNs: (i) Can hESC-MSNs improve function in rodent HD models? We use a sophisticated battery of motor/cognitive tests, first in a widely-used lesion model of HD to comprehensively compare hESC-MSN grafts against the benchmark foetal cells, and second in a transgenic HD rat model; this is a more challenging, but more representative, model of the disease process. (ii) We use a range of approaches to test whether hESC-MSNs make functional synapses with host neurons: slice electrophysiology, DREADDS and rabies transsynaptic tracing. (iii) We will perform scRNAseq to compare hESC-MSNs with their foetal counterparts to assess their degree of heterogeneity, and assess how closely hESC-MSNs and foetal-derived MSNs resemble each other. We will also perform scRNAseq on dissociated mature hESC-MSN and foetal grafts to ask similar questions.  This information will guide the route to the clinic as well as guiding the optimisation of next generation donor cells.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.2 CELLULAR AND GENE THERAPIES
Health Categories: NEUROLOGICAL
Award Title: Cellular mechanisms of viral gene sensing and silencing
Funder: Wellcome Trust

Abstract: Viruses depend on cellular machinery to express and replicate their genes. Viral RNA must therefore be delivered or generated in the cytosol. Some viruses also deliver genomic DNA into the nucleus, for integration into the host cell genome. The cell’s principal innate defenses are to mount a potent inflammatory response upon sensing cytosolic viral RNA and to repress the transcription of integrated viral DNA. To be effective, these responses must be sensitive, specific and appropriately calibrated to minimize toxicity and autoinflammation. Our overarching goal is to gain a molecular understanding of how the cell recognizes cytosolic viral RNA and how it silences viral gene expression with the necessary sensitivity and specificity. In pursuit of this goal we are applying a complementary set of biophysical, biochemical and cell biological approaches, with a focus on using high-resolution structural information to obtain detailed mechanistic insights with atomic-level detail.   Our key goals are to understand:  -how cells distinguish viral from endogenous nucleic acids; -how the immune response against double-stranded RNA is generated and amplified;  -how cells recognize and silence integrated viral DNA;  This will provide invaluable insights on fundamental principles of host-pathogen recognition, chromatin regulation and host-virus coevolution.

Lay Abstract: Viruses deliver their genomes to host cells either as DNA or RNA. The cell’s principal defenses are to mount a potent immune response to viral RNA, and to prevent gene expression from viral DNA. These responses must be finely balanced as their inappropriate activation has been linked to severe autoimmune diseases including Aicardi-Goutières and Singleton-Merten syndromes. To be able to control these responses, we must first define the underlying mechanisms required for activation. We will use a complementary set of approaches to gain a view of how cells interact with viral genomes with unprecedented structural detail. High-resolution structural information has a powerful ability to generate insights into how molecules work and guide the design of potential therapeutics. Our work will establish fundamental principles of how cells calibrate their antiviral responses to prevent virus proliferation without triggering autoimmune responses. We expect to identify new pathogen vulnerabilities and suggest new therapeutic strategies.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Centre for Adolescent Rheumatology Versus Arthritis at University College London (UCL), University College London Hospitals (UCLH) and Great Ormond Street Hospital (GOSH) NHS Trusts
Funder: Versus Arthritis

Abstract: This proposal is to support renewal funding for the Arthritis Research UK Centre for Adolescent Rheumatology at UCL, UCLH and GOSH. 

Adolescents with inflammatory rheumatological conditions have significant, specific unmet needs, related not only to clinical care and transition between paediatric and adult care settings, but also, of central importance for the Centre, due to lack of knowledge and prior research specific to the biology, disease patterns and treatment responses in this distinct age group. Since 2012 we have built a thriving multidisciplinary Centre, and enabled establishment of a National Network, to address these unmet needs. The Centre has leveraged significant new funding, brought in key expertise through collaborations, and developed in-depth patient involvement.

Our goals in the next 5 years are to drive forward research in 4 key areas:
Mechanisms of adolescent-related arthritis;
Biology of the adolescent immune system in relation to inflammatory disease;
Improving health care provision and enabling self-management in young people with inflammatory diseases;
The Barbara Ansell National Network for Adolescent Rheumatology.

In parallel we will secure the next generation of researchers in this growing area, to ensure sustainability of the Centre, while enhancing patient involvement at every level of Centre activity.


Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Changes in gut microbe-host interactions and their impact beyond the gut
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The intestinal microbiota is resilient to change, with alterations in community composition and activity occurring as a result of exposure to various environmental factors and insults such as diet, drugs (antibiotics), infection, surgery and lifestyle. Such changes are being increasingly associated with a number of chronic diseases including those affecting organ systems such as the liver, musculoskeletal system and the brain. In particular, there is an increasing appreciation of the role gut microbes play in influencing liver function and central metabolism (the gut-microbiome-liver axis) and brain development and function (the gut-microbiome-brain axis), which may provide future treatments for serious degenerative diseases. Key observations linking the gut microbiome to mental health and chronic age-related neurodegenerative conditions include demonstrating a relationship between diet-related changes in the gut microbiota and altered cognitive flexibility, the ability of key microbial metabolites to influence the physiology of the blood brain barrier, and alterations in neurotransmitter production by gut bacteria. However, the majority of studies to date suffer from being correlative and providing few mechanistic insights. The expertise and track record in commensal microbiology and gut and liver physiology of QIB-based research leaders and in the enteric nervous (ENS) and endocrine (ES) systems provided by our HEI-based partners, provides the skills, expertise and experimental systems required to undertake the mechanistic studies necessary to define the relationship between gut microbes and other organ systems central to human health._x000D__x000D_
Theme 2 will address how changes in microbiota-host interactions in the gut impact on the functionality of other organ systems including the liver and the brain._x000D__x000D_
This theme involves a 360-participant longitudinal population based study of age-associated changes in the intestinal microbiome in elderly individuals stratified according to their risk of developing dementia._x000D__x000D_
_x000D__x000D_
Theme 2 Outputs To provide: _x000D__x000D_
(1) an improved mechanistic understanding of the bidirectional interactions occurring at the mucosal interface in the ageing gut to help develop strategies that_x000D__x000D_
improve intestinal barrier function. _x000D__x000D_
(2) new multiscale models of the dynamics of the gut system and of the microbiota. (3) new, systems-level and mechanistic insights into how ageing influences the_x000D__x000D_
microbiota and its role in endocrine and neuronal signalling pathways. _x000D__x000D_
(4) establish links between the intestinal microbiome and age-associated declines in mental health.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: ORAL AND GASTROINTESTINAL