NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Neural mechanisms of learning, planning, and decision-making
Funder: Wellcome Trust

Abstract: This proposal examines the neural mechanisms supporting decision-making and prospective planning. We will examine how prefrontal cortex (PFC), hippocampus, and entorhinal cortex (EC) interact to support these processes. We will examine how non-human primates (NHPs) make choices in large decision spaces, particularly when novel choice-values have to be inferred ‘online’. We will test different models of value-coding, particularly whether PFC uses a ‘place-like’ and ‘grid-like’ code to construct cognitive maps of values spaces. We will examine how NHPs make ‘online’ choices when sequentially navigating between stimuli/states as rewards move or paths blocked. We will test whether ‘replay’ provides a neural mechanism supporting model-based planning. We will use Transcranial Ultrasound Stimulation to selectively disrupt regions of PFC/hippocampus/EC to examine its effect on neural selectivity and behaviour. These tasks are high-dimensional, yet amenable to mathematical description, and will be combined with high-density recordings to map these computations. Exp.3 will integrate our home-cage training system with wireless data-logging to record neural data continuously, across tasks and sleep, to examine how neural signatures change across days with learning, and acquisition of ‘learning set’. This provides the technology to continuously map the NHP brain during performance of diverse and naturalistic tasks, radically transforming primate neuroscience.

Lay Abstract: Learning a model of an environment (‘cognitive map’) is critical for decision-making. For example, learning about the London Underground not only facilitates daily transport, but knowing its model features (i.e., use of ticket machines, station maps, transfer stations) provides generalizable knowledge for novel environments (e.g., using the Paris Metro). The ability to use cognitive maps depends on the prefrontal cortex, hippocampus, and entorhinal cortex; dysfunction here impairs learning, memory and decision-making. Developing causal mechanisms of why brain dysfunction disrupts these cognitive processes requires invasively mapping the functional circuitry at the single-neuron level; doing them in a non-human primate is crucial, given their brain is most similar to human. My research examines how neural computations in these areas supports decision-making and construction of cognitive maps, and how disrupting these circuits impairs behaviour. These findings will provide mechanistic accounts of decision-making circuitry, to inform approaches for treatment in psychiatric studies.

Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Neurobehavioural genetics. Isolation and characterisation of behavioural mutations in mice
Funder: Medical Research Council

Abstract: Genetic approaches provide a powerful means by which to examine the biological basis of nervous system diseases such as dementias, neurodegenerative disorders and affective disorders as well as the physiological processes that are affected by them. Almost all mental illnesses are accompanied by abnormal physiological and neurological characteristics that can be readily observed in mice. Phenotype-based approaches have been used successfully in organisms such as Drosophila melanogaster in establishing a genetic basis for many behavioural processes. Use of the chemical mutagen ENU along with hierarchical screening protocols has indicated that phenotype-based approaches in the mouse will be useful in gaining a molecular insight into complex mammalian behaviours.||One of the goals of this group is to identify and characterise ENU-induced mutations that affect specific behavioural processes. The first class of mutations being screened for are those which affect the mammalian circadian clock. The circadian system can be divided into three basic components - the input or entrainment pathway, the central pacemaker and the output pathway. Disruption of any of these components could be responsible for rhythm and sleep anomalies associated with complex psychiatric disorders. Pacemaker function is generally assessed by measuring an identifiable component of the output pathway such as locomotor (wheel-running) activity. The second class of mutations being screened for are those that affect learning and memory. Using these screens, we can identify not only molecular components specifically associated with memory formation but also components associated with neural mechanisms such as migration, plasticity and degeneration.||Paradigms such as Spontaneous Alternation, Novel Object Recognition, Holeboard exploration and Attention testing screens are being used to identify potential mutants. Positional cloning of several mutations identified in these screens is currently underway. This approach is complemented by carrying out molecular analysis of novel mutations. Primarily this involves histological analysis and in situ hybridization of brain regions suspected to be associated with particular behaviours. For example, circadian rhythms are associated with a brain region called the suprachiasmatic nucleus, located in the hypothalamus and consisting of approximately 10,000 cells. Histological analysis tells us whether there is a gross dysmorphology associated with the mutation, indicating that underlying neurodevelopmental processes might be affected.||In addition, by using specific molecular markers known to be associated with a particular behaviour, we can determine the molecular consequences of each mutation. Systematic approaches to characterising molecular pathways associated with behavioural traits are being established.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Non-Clinical Training Award Cycle 4 2018
Funder: Cancer Research UK

Abstract: Non-clinical training at a CRUK centre: At the Institute of Cancer Research researchers are refining radiotherapy for many types of cancer. They are focusing on cancers including sarcomas (cancer of bone, fat, muscle or cartilage), head and neck cancers and children?s cancers._x000D_
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The Cancer Research UK Centre at The Institute of Cancer Research and The Royal Marsden is part of a national network of centres funded by Cancer Research UK with the aim of delivering world-leading translational research and improved patient care.   Funding to the Cancer Research UK Centre was renewed in April 2014 and supports innovative translational research activities at the ICR and The Royal Marsden aimed at delivering precision cancer treatment. Research infrastructure funding to our joint Drug Development Unit forms a large part of the centre funding and will help expand the number of investigator-initiated trials we undertake and the sequencing analysis of patient samples from these trials. Radiotherapy physics research within the centre is focused on the development of integrated treatment and imaging technologies, preclinical studies of radiation-induced biological effects on tumours and healthy tissues, and the translation of technologies into clinical practice. The aim of this research is to develop the most efficient and accurate radiation treatments. An Informatics Facility has been established to capture, analyse, model and integrate data from across the centre. This is comprised of interdisciplinary staff and includes statisticians, bioinformaticians, computer scientists, data modellers and web developers. Training of the next generation of cancer researchers is also a vital component of the Cancer Research UK Centre with funding provided for clinical and non-clinical PhD training programmes. _x000D_
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The centre recognises the importance of engagement activities to encourage the talent of the future and help make young people aware of opportunities for careers in cancer research. We are developing activities designed to engage with school-age students and support their national curriculum learning activities._x000D_
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http://www.icr.ac.uk/our-research/our-research-centres/cancer-research-uk-centre


Research Activity Codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health Categories: CANCER AND NEOPLASMS
Award Title: Non-Clinical Training Award – Cycle 3 – 2017
Funder: Cancer Research UK

Abstract: Newcastle Cancer Centre at the Northern Institute for Cancer Research: Non-clinical training_x000D_
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Newcastle has now joined the charity's unique network of 'virtual' centres delivering world-class science and improved patient care. The new Centre puts Newcastle at the forefront of cancer research and will bring benefits to patients in the North East._x000D_
The Centre is not a new building, but instead is a collaboration between Cancer Research UK, the Leukaemia Research Fund and the North of England Children's Cancer Research Fund. This will make it easier for scientists to work together with doctors and nurses, so patients can benefit from research breakthroughs more quickly._x000D_
Research at the Centre will concentrate on understanding the basic biology of how and why cancers develop, with a particular focus on blood cancers, such as leukaemia, and childhood cancers._x000D_
Scientists in Newcastle have an impressive track record in the discovery and development of new anti-cancer drugs. Researchers at the new Centre will focus on developing treatments that can be tailored to the genetic 'signature' of an individual cancer patient, instead of a one-size-fits-all approach. This will help to avoid unnecessary side effects and improve survival rates._x000D_
Clinical trials are an important aspect of the Newcastle Centre for Cancer Research. Through this initiative, we aim for more cancer patients in the North East to be given the opportunity to take part in trials of the latest treatments.


Research Activity Codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health Categories: CANCER AND NEOPLASMS
Award Title: Novel Genome Integrity Pathways that regulate DNA Replication Termination in Metazoa
Funder: Cancer Research UK

Abstract: Background:

 The mechanisms of chromosome replication preserve genome integrity and are fundamental to our understanding of cancer development.
Moreover, DNA replication regulation provides multiple opportunities for new cancer treatments.
 The key step during initiation of chromosome replication is the assembly at replication origins of the DNA helicase known as CMG (CDC45-MCM-GINS), around which the replisome is assembled.


 Subsequently, CMG is stably associated with replication forks throughout elongation, but then is disassembled in the final step of DNA replication termination, leading to dissolution of the replisome.
Recent work indicates that DNA replication termination is regulated by ubiquitylation of the CMG helicase, leading to replisome disassembly in a process requiring the CDC48/p97 ATPase.
The E3 ubiquitin ligase and other factors that regulate replisome disassembly in higher eukaryotes have not been reported previously.

Aims:

 This proposal explores the hypothesis that metazoa contain multiple genome integrity pathways that regulate DNA replication termination.
The first pathway acts during S-phase, whereas the other mechanisms provide important backup during mitosis, ensuring that the DNA replication machinery is completely disassembled, before chromosome segregation and cell division.

Methods:

 We will use the early embryo of the nematode C. elegans to identify and analyse the ubiquitin ligase that regulates replisome disassembly during DNA replication termination in metazoa.
We will explore how the ligase is targeted to the replisome, and investigate the functional implications of replisome disassembly for genome integrity.

 Similarly, we will screen for factors that mediate backup pathways for replisome disassembly during mitosis, and then investigate how these factors are regulated, in order to preserve genome integrity.

 Finally, and guided by our study of replisome disassembly in the worm, we will investigate the E3 ligase and other factors that control DNA replication termination in mammalian cells.

How the results of this research will be used:

 If successful, the delineation of multiple pathways for replisome disassembly in metazoa (worm/mouse/human), and the identification and functional analysis of various key players, will identify new candidates for potential future therapies.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Award Title: Novel perimetry for identifying changes in visual field sensitivity in glaucoma
Funder: Medical Research Council

Abstract: Glaucoma is a chronic, progressive, degeneration of retinal ganglion cells, characterised by slow, irreversible loss of the peripheral visual field. Prognosis for vision is highest the earlier it is identified and treated. Perimetry, the clinical method for identifying visual field loss involves presenting stimuli (spots of light) to the retina to determine the dimmest that can be detected at multiple locations in the field. However, this technique has major limitations: a) low sensitivity to early damage, and b) high variability in moderate damage, making it difficult to identify further deterioration in those already diagnosed. The conventional test was developed >40 years ago, before the pathophysiology of glaucoma was understood, and has remained relatively unchanged since. With a design that is effectively arbitrary, it is unsurprising that glaucomatous changes are difficult to detect with the current standard clinical test. We recently discovered two functional biomarkers for glaucoma (changes in spatial and temporal summation) which will allow a redesign of perimetry for more accurate and precise measurements of changes in the visual field. In this multi-disciplinary, UK-wide, multi-site, project, we will initiate the path for translation of a novel, more evidence-based form of perimetry from laboratory to the clinical setting. This initial phase of the work will involve optimising clinical test parameters to maximise accuracy, test precision and efficiency in the novel test.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: EYE
Award Title: Novel statistical methods for transcriptomic imputation to enhance understanding of causal mechanisms underlying human diseases
Funder: Medical Research Council

Abstract: Integrated analysis of genetic variation and transcriptomic data resources from large-scale tissue-based molecular profiling initiatives has improved understanding of the biological mechanisms controlling the regulation of gene expression across diverse tissues through the identification of expression quantitative trait loci (eQTL). Methods have been developed to detect association of complex traits with gene expression by: (i) building tissue-specific multi-eQTL models in these molecular profiling resources; and (ii) using these models to "impute" the transcriptome into genome-wide association studies (GWAS). However, existing transcriptome imputation methods typically: (i) do not take advantage of the observed correlations in expression between cell types driven by cross-tissue eQTLs; and/or (ii) do not account for eQTL model uncertainty, resulting in potential for over-fitting and increased false positive error rates. The overall aim of this proposal is to develop novel statistical methodologies for transcriptomic imputation into GWAS to address these limitations by harnessing multi-tissue expression to detect causal genes for complex human traits in a Bayesian Markov chain Monte Carlo framework to allow for model uncertainty. The methodology will be implemented in user-friendly and computationally efficient software, which will be applicable to individual-level genotype data or association summary statistics. The methodology will be applied to create a repository of imputed cross-tissue transcriptomic profiles across genes for all participants in the UK Biobank, which will be tested for association with rheumatoid arthritis and other musculoskeletal diseases, cardiovascular disease, cancer and diabetes. The repository will also be returned to UK Biobank for archiving and distribution to approved researchers to identify causal genes for any trait of interest available in the resource.


Research Activity Codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Novel strategies to improve the effectiveness of radiation and targeted therapies in lung cancer
Funder: Medical Research Council

Abstract: Lung cancer is a devastating disease and the leading cause of cancer death worldwide. The most common form of lung cancer is non-small cell lung cancer (NSCLC) and patients with early stage disease can be treated with surgery or radiotherapy. However, most NSCLC patients present with locally advanced or metastatic disease. In these cases, chemotherapy, with or without radiotherapy, forms the cornerstone of treatment. Unfortunately, the prognosis remains poor for these patients, despite the development of novel therapies targeted to specific oncogenic drivers (e.g. EGFR, ALK, ROS, RET). Therefore, this programme aims to identify and evaluate novel therapies and targets for their potential to improve outcomes in lung cancer. The areas of focus for this programme are (i) improving the therapeutic margin of radiation by combining with drugs that either modulate the radiation-induced DNA damage response (DDR) or reduce radiation-induced lung toxicity (RILT), (ii) understanding the biological responses of normal cells in the lung when exposed to radiation alone or in combination with DDR inhibitors, (iii) identifying new targets to improve the effectiveness of radiation therapy, and (iv) identifying approaches for combining DDR inhibitors with targeted therapies (without radiation) for potential use in metastatic disease where chemotherapy (with or without combination with targeted therapies) forms the backbone of treatment. The development of DDR inhibitors has progressed rapidly since the demonstration that PARP inhibitors show clinical benefit in patients with BRCA1/2 mutated tumours. This has stimulated the development of inhibitors targeting other components of the DDR, including Ataxia Telangiectasia mutated (ATM) and Ataxia Telangiectasia and RAD3 related (ATR). DDR inhibition is an attractive strategy to improve the effectiveness of radiation, but there remains uncertainty about increased normal tissue toxicity and how to select which DDR approach to use in a particular setting. This program aims to clarify how different classes of DDR inhibitor affect tumour and normal lung tissue, and to identify the DDR approaches that have the potential for the greatest therapeutic margin in lung cancer. Impact: This project will identify and characterise novel combination approaches for the use of DDR inhibitors in NSCLC patients with systemic/metastatic disease. This work will broaden the utility of DDR modulators from combinations with radiation and cytotoxic chemotherapy, to include combinations with cell signalling inhibitors which have greater potential for selective biological effects in tumour cells compared with normal tissues.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Nudge based intervention supported by real time data analytics to improve mechanical ventilator wean – guiding clinical behaviour (ATTITUDE study)
Funder: The Health Foundation

Abstract: Patients in intensive care units (ICU) are the most vulnerable of hospital patients and need close monitoring and delicate administration of complex therapy. Critical care therapies such as mechanical ventilation can save lives, but inappropriate use is associated with patient harm. Ventilator-induced injury, excessive fluid administration, uncontrolled oxygen therapy and inappropriate sedation can all worsen outcomes.

This project aims to use behavioural insights methods to find out whether real-time data analytics and use of a clinical decision support tool can improve the quality of key critical care practices in an adult ICU.

It will begin with a review of the existing evidence on the perceptions of clinical decision support aids in health care. The team will then survey doctors and nurses at Royal Victoria Hospital to find out what barriers there are for weaning, oxygen administration, sedation and fluid balance. They will also observe current practice.

A behavioural intervention in the form of a clinical decision support tool, driven by real-time data analytics, will then be developed to ‘nudge’ practice, based on identified barriers. There will be other supportive interventions such as educational support if knowledge gap is identified as a barrier.

The overall aim is to achieve a significant reduction in the duration of weaning. Improvement in care for patients on mechanical ventilators would lead to improved patient outcomes, including mortality, and reduced health care costs by a reduction in intensive care unit and hospital stay.


Research Activity Codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Nutrient competition and metabolite production by the gut microbiota to reduce carbapenem-resistant Enterobacteriaceae growth in the human intestine
Funder: Medical Research Council

Abstract: Antimicrobial resistance is a serious threat to human health, resulting in treatment failures, infection relapses, longer hospitalisations, and poor clinical outcomes. The intestine is the primary colonisation site for carbapenem-resistant Enterobacteriaceae (CRE) and serves as a reservoir for CRE responsible for invasive infections (e.g. bloodstream infections). Antibiotics promote CRE intestinal colonisation and faecal microbiota transplantation (FMT) decolonise CRE from the gut. However, there are drawbacks to administering FMT to CRE colonised patients, and FMT needs to be replaced with new therapies that are more effective, safe, rationally designed, and doseable. I hypothesise that antibiotics kill gut microbiota members that compete with CRE for nutrients and/or produce inhibitory metabolites, creating a niche in which CRE can grow. I will develop new microbiome therapeutics consisting of a synthetic microbial consortium and inhibitory metabolites. Inhibitory metabolites will cause an initial reduction in CRE growth. The synthetic microbial consortium will colonise the intestine, outcompete CRE for nutrients, and inhibit CRE growth by producing inhibitory metabolites, resulting in a long-term reduction in CRE growth. An artificial gut model of CRE intestinal colonisation will be used to determine the effects of antibiotics and FMT on nutrient competition, metabolite production, microbial composition, and CRE growth in a faecal microbiota. Synthetic microbial consortia will be designed consisting of gut microbiota members that outcompete CRE for nutrients and produce metabolites that inhibit CRE growth. These new therapeutics will be tested in the artificial gut model to demonstrate their efficacy to inhibit CRE growth in faecal microbiota. This study has the potential to significantly impact clinical practice by developing a new treatment that could be used to prevent or treat CRE intestinal colonisation, and therefore prevent invasive infections.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: INFECTION;ORAL AND GASTROINTESTINAL