NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Core Funding Extension for the Wellcome Centre for Human Genetics
Funder: Wellcome Trust

Abstract: We are a research community of basic and clinician scientists on an inter-disciplinary hospital campus with extensive outreach to Oxford’s tropical medicine units and global health challenges. Our vision is improving human health by maximising the informativeness of human genetics and disease mechanisms.  We commit to: Responding to clinical need, making discoveries in biology to investigate genome function, translating them to molecular-cellular structures and mechanisms, and investigating impact of variation between individuals and cells, with disease and clinical outcomes. Enabling through technology, using genetics/genomics, bioinformatics, structure determination, computing, and cell/mouse genome editing, underpinned by world-leading core facilities, to understand human physiology and pathology. Data, results, materials, software, and knowhow are made fully accessible.  Translating knowledge to the clinic and, where appropriate, filing patents and establishing partnerships, within the University and wider academic, technology, and biomedical sectors. Promoting a positive research culture and building capacity in people and expertise, for all staff, including enabling early-career researchers to test ideas and flourish with essential support from our core facilities. This extension will enable us to capitalize on, and extend, significant innovations since 2016, developing the next generation of innovative, game-changing technologies, approaches, and researchers, to meet still-existing and emerging threats to health.


Research Activity Codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Coupling of transcription with other cellular processes
Funder: Wellcome Trust

Abstract: The first two steps of gene expression are tightly coupled in both bacteria and eukaryotes, which largely determines outcomes of gene expression. Transcription-translation coupling in bacteria is essential for viability and virulence. Transcription-splicing coupling in eukaryotes is critical for development and differentiation, and its malfunction may lead to disease. However, little is known about the molecular details of these mechanisms, mainly due to the absence of tractable experimental systems. We developed a unique in vitro transcription-translation coupled system, which we will use to investigate interactions of RNA polymerase with ribosome, how transcription regulates initiation of translation, and how ribosome controls RNA polymerase activities, transcription pausing and resolves transcription events that compromise genomic integrity. By using the first in vitro transcription-splicing coupled system, we will study direct interactions of RNA polymerase II with spliceosome ribonucleoprotein particles, how transcription elongation regulates assembly of the spliceosome and alternative splicing, and regulation of elongation by spliceosomal complexes, which is critical for splicing efficiency. In vitro programme will be complemented by new NGS-based techniques and CryoEM analysis of transcription-translation and transcription-splicing coupled complexes.  The results will enrich our understanding of basic molecular processes that underpin many human diseases, and may provide new targets for antibiotics.

Lay Abstract: The first step of gene expression, transcription, is tightly coupled to the next step. In bacteria, coupling of transcription to translation is essential for survival and virulence, and thus could be a target for antibiotics. In eukaryotes, coupling of transcription and splicing is critical for development and differentiation, and dysregulation of coupling may cause serious diseases. Molecular mechanisms of coupling of these important processes are, currently, beyond reach due to the absence of tractable experimental systems. We have developed a unique in vitro system for studying transcription-translation coupling, and are reconstituting the first in vitro coupled transcription-splicing system. We will use these experimental systems, complemented by novel next-generation-sequencing-based and structural techniques to reveal the details of cross-talk and mutual regulation between these fundamental processes. The results will help understand transcription-translation and transcription-splicing coupling in more mechanistic and global terms, and provide information on new antibiotics targets and mechanisms of disease.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Creating a UK Colorectal Cancer Intelligence Hub - Supported by the Bobby Moore Fund
Funder: Cancer Research UK

Abstract: Background:
High-quality data improve cancer outcomes. Good intelligence underpins patient choice, helping individuals reduce the risk of disease and access the best care. It identifies and quantifies inequalities, improves the cost-effectiveness and quality of services and supports cancer research. Unfortunately, the availability of such high-quality cancer intelligence has been limited; this programme of work seeks to rectify this by robustly linking and analysing multiple routine data sources to enable scrutiny of the performance of the National Health Service (NHS).

Aims:
 The aim is to quantify the characteristics of, and any variation in, colorectal cancer and its management across the UK and so provide the evidence required to guide interventions that will eliminate inequalities and improve survival from the disease.
 This will be done by
 1. Developing an accessible UK COloRECTal cancer Repository (CORECT-R) within which all available routine datasets relevant to colorectal cancer will be linked at a patient level.
2. Pioneering the development and application of appropriate statistical methodologies to analyse the complex data within CORECT-R.
3. Analysing the content of CORECT-R to quantify inequalities and identify processes and procedures associated with best practice and improved patient survival
4. Promoting the use of CORECT-R to inform translational research, clinical trials, and other areas of cancer research.
5. Collaborating with a directly engaged community of patients, charities, data users and policy makers to ensure the resource, and the work it enables, has the highest clinical relevance and impact

Methods:
 The programme will span four areas. Workstream 1 will establish the Programme Advisory Group and engage with all who have a stake in UK colorectal cancer care.
Workstream 2 will establish CORECT-R, Workstream 3 will focus on the optimal methods to exploit it and workstream 4 will constitute exemplar projects illustrating what the data will enable. These exemplar projects will focus on supporting earlier diagnosis, quantifying inequalities, optimising treatments and promoting the use of big data to support clinical trials and translational research.

 How the results of this research will be used:
 The outputs of the research will be used to reduce inequalities and improve survival from colorectal cancer.
Although this programme of work is focused on colorectal cancer, the methods and techniques developed will be directly applicable to other cancer sites and, potentially, other diseases. The programme thus has potential to improve outcomes for all patients in the NHS


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Award Title: Creating a federated cloud-based TRE to facilitate consortium-based research and interoperability between existing institutions/TREs
Funder: Medical Research Council

Abstract: Current TREs are generally centred around a thematically consistent group of datasets, owned by a singular institution1. Each has its own computational infrastructure, security arrangements, access management and so on. Researchers need to a) know that the TRE exists, b) know what data is held in it c) have to apply individually per project for access d) have access to their own local, secure environment in which to work with the data. In some cases, d) is not viable due to data sensitivity limiting work to tools provided in the TRE. In all cases, working with data in a TRE is bureaucratically laborious and often scientifically limited, as the ability to work with data sets across TREs, or most importantly, in conjunction with locally collected experimental data, is difficult, or sometimes, impossible. Rather than building another TRE ‘silo’, we will demonstrate a series of components interworking to form a scalable ‘virtual TRE’ or vTRE architecture. This is centred around  a  multi- cloud ‘data fabric’, built using the commercial SnowflakeTM platform, which offers a powerful toolset for managing security, data sharing and access in a very flexible way. It also has the advantage of extreme scalability, as it is built on the huge resource pools available on AWS, Google and Azure public clouds, allowing for TREs to be easily defined in ‘Infrastructure as Code’ terms, rather than as capitally intensive physical environments. Unlike other cloud-based technologies, SnowflakeTM is unique in being a single data fabric shared between customers, rather than discrete databases which necessitate local access and security controls. Rigid and specific data sharing is enabled and simultaneously makes possible ‘immediate’ access to any approved SnowflakeTM account, with a marketplace to help discovery and public sharing of any appropriate datasets. This work will build an illustrative data environment, enabled to connect the Crick and partners with sample data. Around this data fabric, we will build modular components to demonstrate the principles of creating a stand-alone ‘access-as-a-service’ platform, which any TRE could use to centralise access workflows and requests. This will be connected to an illustrative policy library and provisioning engine to automatically ‘spin up’ pre-defined TRE environments, removing administration whilst ensuring rigour of definition, security and access control.


Research Activity Codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Creative ageing and social prescribing: Bridging the gap between diverse service users, service providers and policy makers in Wales
Funder: The British Academy

Abstract: Social prescribing is a non-pharmacological approach to supporting people’s health and wellbeing through referrals to meaningful activity such as the arts. In the UK it is a key policy area linked to the personalised healthcare agenda which aims to cut the booming cost of an ageing population. The applications of ‘arts on prescription’ are complex and often exclusive of the communities that need interventions the most. Particularly, when engaging older adults with experiences of social isolation and/or dementia, there are barriers such as digital literacy, access to devices, capacity to consent, cultural and aesthetic preferences. Creative practitioners and service users hold most of the information on impact - it’s a predominantly oral, experiential and private body of knowledge. Ethnographic and participatory approaches are therefore highly suited to document and translate this knowledge to policy makers. This will contribute to cost-effective solutions tailored to the specialised needs of our ageing population.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Cryo focussed ion beam scanning electron microscope for correlative functional studies of biological systems in situ by tomography
Funder: Wellcome Trust

Abstract: Dramatic advances in cryo-electron microscopy (EM) have greatly enhanced macromolecular structure determination. The current frontier is in situ cellular structure determination to understand the machinery of life operating in the native biological environment. Visualising the native structure of cells and tissues by cryo-electron tomography requires the preparation of cryo-samples ~100-600 nanometers in thickness. The vitrified tissue sections must be thin enough to allow penetration by the electron beam, yet thick enough to contain complete structures of biological relevance. Although cells and tissues can be sectioned in the vitreous state by cryo-ultramicrotomy, both section thickness and quality are severely limited by mechanical damage including deformation, non-uniform compression and crevassing.
 
The only available method able to precisely modify the thickness of frozen-hydrated samples and balance these conflicting requirements is focussed ion beam (FIB) milling in a scanning EM. FIB milling provides access to the cell interior, within otherwise unperturbed cellular environments, yielding vitrified lamellae suitable for electron tomography and unaffected by compression forces. Here we request a cryo FIB field emission gun scanning EM (FEG SEM) to produce lamellae targeted to fluorescent features of interest for transfer into a cryo-transmission EM (TEM) for three-dimensional (3D) structure determination by electron tomography.

Lay Abstract: Current electron microscopes can resolve fine details of cells and molecules, enabling us to observe the machinery of life in operation, revealing mechanisms of action and new therapeutic targets. However, transmission of the electron beam requires samples much thinner than a typical cell. This poses a major challenge, since the goal is to observe cells in their native, frozen-hydrated state.

Mechanical cutting of frozen material causes considerable damage, distortion and lacks sufficient volume for three-dimensional modelling.  A new approach proffering control and precision has been developed, in which material above and below the layer to be observed is ablated by an ion beam. Although slow, this is the only way to get suitable layers of cells and tissues for high-resolution electron microscopy. This application seeks funding towards a dual-beam scanning electron microscope that will enable us to prepare samples under cryogenic conditions for high-resolution electron tomography of native, cellular structures.

Research Activity Codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;1.4 METHODOLOGIES AND MEASUREMENTS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: DNA methylation of different brain cell types in Parkinson’s disease
Funder: Wellcome Trust

Abstract: Parkinson’s disease is an increasing global concern, affecting one in twenty people by age 85 and costing the NHS more than £1 billion/year. The underlying mechanisms are still almost completely unknown and there are no drugs that can cure the disease. In addition to traditional genetics, recent work in Parkinson’s has focussed on epigenetic variation, in particular DNA methylation in the brain. However, even though different brain cell types are affected by Parkinson’s in different ways, all previous work has only considered bulk brain tissue consisting of a mixture of cell types. For the first time, this project will determine the DNA methylation profile in individual cell types of the prefrontal cortex in both people with Parkinson’s and matched controls. In particular, this will include separate analysis of neurons, oligodendrocytes and other glial cells. This will generate pilot data that will lead to several large (>£1M) follow-up grant applications, including not only studies of DNA methylation, but single-cell-type investigations of other epigenetic marks such as histone modifications and non-coding RNAs. The hope is that this approach will lead to a step change in the mechanistic understanding of Parkinson’s disease, and produce a host of new potential drug targets.

Lay Abstract: By age 85, one in twenty of us will be affected by Parkinson’s. What is more, the disease will only become more and more common as we continue to live for longer and longer. However, we still know very little about Parkinson’s and there is currently no cure. Although most previous research has looked at how DNA changes cause Parkinson’s, we have recently started to realise that other types of changes (so called “epigenetic” changes) play a crucial role. However, despite this, all previous work in this area has only ever looked at whole brain regions at the same time. In this project, for the first time, I will look at epigenetic changes in Parkinson’s in separate types of cell. I believe this has the potential to revolutionise research into Parkinson’s, leading to much better understanding of the disease and, more excitingly, suggesting new types of drug treatments.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Deciphering inherited susceptibility to childhood cancer (co-funded by Children with Cancer UK)
Funder: Cancer Research UK

Abstract: Background: The identification of cancer-predisposing genes (CPGs) is of increasing importance in paediatric oncology for the diagnosis, treatment, surveillance, family counselling and research. Although many childhood cancers are associated with CPGs the number caused by inherited vs. de novo mutation and the total number of genes which are true CPGs is unknown.

Aims: To identify new CPGs and decipher the contribution of inherited predisposition to paediatric cancer.

Methods: We will perform family-based genetic analyses of the germline of children with diagnosed with Wilms tumour, Ewing sarcoma, rhadomyosarcoma, glioma, meduloblastoma or Neuroblastoma. Specifically, we shall analyse multiple case families and parent-offspring trios using NGS and array technology.

How the results of this research will be used: This work should reveal a striking new landscape of inheritance in childhood cancer and inform personalized and preventive medicine and cancer surveillance programs.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Deciphering the Genomics of Aggressive non-Hodgkin Lymphoma
Funder: Cancer Research UK

Abstract: Background
To unravel the biological basis of aggressive non-Hodgkin lymphomas (aNHL), we and others have performed large mutational profiling studies. These reveal considerable genetic heterogeneity and identify hundreds of recurrent genetic alterations. These mutations are not independently distributed, allowing cases to be clustered into predicted genomic subtypes. Gene expression and survival differences support the concept that these subtypes represent biologically distinct diseases, suggesting optimal treatment may differ between subtypes. There is no shortage of novel, therapeutic agents in development for lymphoma. However, it remains far from clear how these should be targeted to molecular subtypes or individual patients. The large number of theoretical drug combinations, combined with the complex genetic heterogeneity makes it impossible to address these questions by empiric testing in clinical trials. Therefore, we require better preclinical experimental systems to model the effects of mutational repertoires and enable their interrogation. My group has developed a novel experimental system that allows the creation of mutation-customised models of lymphoma, and provides the ability to study many hundreds of mutational combinations simultaneously.

Aims
1) Dissect the GNA13 pathway as a potential therapeutic target in aNHL.
2) Perform comprehensive, combinatorial mutant open reading frame (mORF) screening of 1,000 recurrent mutations in human GC B cells ex vivo and in vivo.
3) Combine genetic perturbation and single cell transcriptional profiling of mORF-transduced single cells with a systems biology model to condense genetic heterogeneity into targetable oncogenic pathways.
4) Develop a highly sensitive plasma DNA sequencing assay to capture the evolution of genetic heterogeneity during lymphoma treatment.

Methods
We will capitalise on a system we developed for ex vivo expansion of primary human B cells in a co-culture designed to mimic the germinal centre microenvironment. Genetic manipulation of lymphoma driver genes allows us to generate immortalised cultures and “synthetic” in vivo models that closely recapitulate aNHL. This will be combined with a lymphoma-specific mutant ORF library and single cell sequencing technologies.

How research will be used
By understanding how genetic alterations co-operate to drive lymphoma and how mutational profiles evolve during therapy, our results will:

1) Elucidate the molecular basis of recently described genomic subtypes
2) Propose therapeutic stratification for future trials
3) Identify the pathways that should be optimally targeted for individual disease subtypes
4) Determine how we should assess response to treatment at the subclonal level.

Results will therefore guide the design and interpretation of the next generation of lymphoma clinical trials.


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: Decoding real tool use from visual fMRI response patterns
Funder: The British Academy

Abstract: The ability of humans to manufacture and use tools is unsurpassed across the animal kingdom, with tool use considered a defining feature of our species. Previous studies that investigate tool use, record brain activity while people view pictures of tools or hands and not when people perform hand movements with tools. But perceiving an image is quite different to acting with a real tool. Recently, we published the first investigation showing that holding an object correctly is represented in brain areas that respond to the sight of hand pictures and not in visual areas that respond to the sight of tool pictures. Here we will investigate whether these visual regions represent specific hand movements during actual tool use. Our work will provide a more realistic understanding of the brain regions involved in tool use, have implications to understanding the impact of brain disease and aid the development of brain-computer interfaces.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: NEUROLOGICAL;MENTAL HEALTH