NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Oesophago-gastric adenocarcinoma: understanding disease pathogenesis and applications to earlier diagnosis
Funder: Medical Research Council

Abstract: Understand the underlying clinical, genetic and cell environmental factors that lead to the conversion of a low-risk pre-malignant state into invasive cancer. Find new diagnostic tools that will identify those patients who are at an increased risk of developing cancer. Improve the molecular characterisation of oesophageal adenocarcinoma and identify novel approaches for tumour classification, monitoring and therapy.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL
Award Title: Oncogenic control of cell division
Funder: Cancer Research UK

Abstract: Background:

During cancer progression, cells encounter a range of physical environments that differ from those experienced by normal cells in a healthy tissue. These include increased interstitial pressure and over-crowding during phases of uncontrolled tissue growth. In addition, during the process of invasion and metastasis, cancer are likely to lose contact with their native ECM and their normal neighbours, and may even experience shear flow. Because of this, the ability of cancer cells to go on to form metastases depends on their being robust to changes in their extracellular environment. 

The potential of physical forces in the environment to perturb cell behaviour is especially high during division. To counter this, both normal and cancer cells tend to round up before they divide. In doing so, they assemble a mechanical rigid actomyosin cortex that provides mitotic cells with the space necessary to assemble a spindle. This is likely to be especially important in cancer cells, both because of the unpredictability of the tumor environment, and because cancer cells frequently need the space to assemble a spindle using multiple centrosomes that is large enough to align extra chromosomes. 

Aims: 

Here, to elucidate the mechanisms by which oncogenes make cancer cell divisions robust and independent of the environment - a likely pre-requisite for metastasis - we aim to determine:

1: How oncogenic signalling influences mitotic rounding, mechanics, and division.
2: How this contributes to the environmental sensitivity of cancer cells divisions.
3. How physical factors and oncogenes influence cell division in tumour spheres and patient-derived tumours.

Methods:

MCF10A::RasV12-ER cells will be used as a model system in which to determine the impact of oncogenic Ras-ERK signalling on division. Microfabrication will be used to build devices to modify the local environment in precisely defined ways to explore the environmental-sensitivity of these divisions (+/-RasV12). Tumour spheres will be used as in vitro models of metastatic tissue. Finally, with colleagues at UCL, we will explore and model the 3D environment experienced by mitotic cells in tumours isolated from patients. 

How the results of this research will be used:

By shedding light on the role of oncogenes in enabling cancer cells to divide in hostile environments that would kill normal cells, we aim to identify weak points that make cancer cells susceptible to perturbations that do not harm normal cells. In doing so, we aim to open a door to future anti-cancer therapies.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: One Health Drivers of Antibacterial Resistance in Thailand
Funder: Medical Research Council

Abstract: Our strategy for investigating drivers of antibacterial drug resistance in Thailand will be first to rank the influence of different material substances and actions that drive the increased prevalence of 3rd Generation Cephalosporin resistant Escherichia coli and Klebsiella pneumoniae, and Carbapenem Resistant Enterobacteriaceae in Thailand. We will do this by quantifying these bacteria and also chemicals (including antibacteirals) in humans, animals, and the environment, and ranking how strongly these chemicals can select for antibacterial drug resistance, and how well the various identified bacteria compete with and/or pass their resistance to other bacteria. We will then ascertain the importance of different actions in determining the abundance of the chemicals and bacteria under study. We will do this by ranking the contribution of different possible sources of resistant bacteria, by measuring the scale of antibacterial use in different human and animal populations and by using risk factor analysis to consider the relative importance of different actions as drivers of enteric colonisation of 3rd Generation Cephalosporin resistant Escherichia coli and Klebsiella pneumoniae, and Carbapenem Resistant Enterobacteriaceae. We will then conduct focused social science research to investigate the social, cultural, and economic drivers associated with antibacterial use and with heightened risks of human exposure to resistant bacteria. These diverse types of data will be used to construct a dynamic multilevel model of resistance transmission and containment. This phased approach will enable us to integrate our workstreams and identify antibacterial drug resistance-reducing interventions with the best likelihood of success. At all stages we will engage with Thai stakeholders and policy makers identified during the development phase, increasing impact


Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: One Health: human responsibility for animal health and welfare in Scotland, 1840-present
Funder: Wellcome Trust

Abstract: This is a collaborative, multidisciplinary project between Edinburgh University Library (EUL) and the Royal Zoological Society of Scotland (RZSS) to catalogue, preserve, selectively digitise and make available for innovative research three significant collections.These collections were identified because of intersections between research, evidence, and debate from different perspectives, human and animal health and well being. The archive collections are from animal protection charity OneKind, Royal (Dick) Veterinary College and Royal Zoological Society of Scotland (RZSS).   The objectives are to:     • create interoperable standards-compliant digitally-online catalogues   • ensure long-term preservation by rehousing collections in archival-quality enclosures;   • carry out interventive conservation work on at-risk items;   • digitise key illustrative material and make available through interactive technology for public and research access;   • design and create a dynamic website for catalogues, providing contextual information for public engagement and research;   • undertake interdisciplinary research using collections, including analysis of datasets;   • engage research communities and wider public through social media, articles, talks, conferences, interventions and engagement events;   • lay the foundations for further projects, funding for research and public engagement, scoping further related collections and forging partnerships with other institutions with related material.   • Create a better understanding of the relationships between human and animal health and changing historical trends and ethical positions.


Research Activity Codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: One cell at a time: building the Human Cell Atlas
Funder: Wellcome Trust

Abstract: The Human Cell Atlas aims to understand cells at a fundamental level and what this means for health and disease. Our ambitious public engagement programme will explore fundamental questions embedded within the HCA research such as “What does it mean to be normal?” and “What influences peoples’ value and trust in research involving tissue donation and open access data?”
 
We have identified audiences with whom engagement with HCA science has particular relevance. These are: 1) patient groups affected by conditions investigated as part of the HCA, 2) existing and potential organ donors, 3) communities not often represented in conversations around healthcare research and organ donation, and 4) education cohorts whose learning experience could be influenced by the research.
 
Our vision through the engagement with our target communities is to improve outcomes related to the value and trust people place in research with consequent impact on willingness to donate tissue for research, share their data and help to identify areas of unmet need that the HCA could tackle.  Our impact also extends to the global HCA consortium, where the methods and resources created and tested through our work will be made available to the wider community.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Opportunity-Led - Developing system-oriented interventions to reduce car dependence for improved population health in Belfast
Funder: Public Health Agency, NI

Abstract: Reducing car dependency has the potential to contribute to several of the Sustainable Development Goals. None of these can be achieved through single component interventions and thus our theoretical framework for developing and testing our proposed intervention(s) will be informed by complex systems science. Our focus will be on communities where car use is high and our assumptions are that dependency is shaped at multiple levels: at the level of the individual and by the social (e.g. norms), urban and political environments. Thus it is necessary to understand influences at the macro (e.g. urban and political environments), meso (e.g. social context) and micro (e.g. individual) levels to devise and sustain effective interventions to reduce car dependency. Further, their integration within community and urban ecosystems must be tied intrinsically and dynamically to social and ecological relations that bear upon transport management policy and governance. The overarching aim of this project is to co-develop sustainable and scalable systems-level interventions at the intersection of (environmental) infrastructure and (individual) agency to reduce car dependency for improved population health.


Research Activity Codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Optimisation of a gene therapy for Oculopharyngeal muscular dystrophy
Funder: LifeArc

Abstract: Around 1 in 100,000 people globally are diagnosed with the genetic condition Oculopharyngeal muscular dystrophy (OPMD) – although rates are higher in some populations.

The condition is caused by defects in a gene that makes PABPN1, a protein that plays a part in several important biological processes. The genetic defects cause the protein to form clumps in cells in the muscles important for lifting the eyelids and for swallowing. It can also affect some arm muscles.

The team has collaboratively been optimising a gene therapy approach based on injecting modified viruses that can act as very efficient carriers (vectors) of DNA into skeletal muscle. The vectors carry information that inhibits the production of all PABPN1 made in the cell and makes new protein without the mutation.

Currently a number of gene therapies are being tested clinically for the systemic whole-body treatment of rare genetic muscle diseases. While the vector the team has collaboratively developed for OPMD works well when injected directly into the muscle, for long term benefit clinicians would need to treat many muscles in each patient. The team is therefore looking to design a new vector to allow whole-body bloodstream delivery to treat multiple skeletal muscles in the body.

The project is using a different vector type with several modifications to the DNA it contains so that it is suitable for skeletal muscle, with the ultimate aim of treating patients with a single injection. This would improve patients’ treatment options, clinical outlook and quality of life.

The team will optimise the DNA that encodes the normal protein that is missing in affected cells and screen cells to find the best performing sequence to include in the final gene therapy product.

They will also screen other regulatory DNA sequences to minimise the expression of the vector in tissues other than skeletal muscle. These new features will be enclosed in a single vector that will be tested by bloodstream delivery in a mouse model of OPMD, allowing researchers to examine improvement in the function of affected muscles.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health Categories: MUSCULOSKELETAL
Award Title: Optimising Immuno-oncology Approaches in Oncology
Funder: Cancer Research UK

Abstract: Background: The MRC Clinical Trials Unit is the largest of its kind in Europe, running practice changing trials in cancer, infections and neurodegenerative disease. A key programme of activity within the MRC CTU is 'affordable and effective cancer care'. Immune checkpoint inhibitors (ICI) are an approach that has revolutionized cancer treatment, stimulating the body's own immune system to control or eradicate cancers, yet as intravenous (antibody) drugs are burdensome to patients and prohibitively  expensive for many health economies.

Aims: I aim to undertake a piece of original work within this programme at the MRC CTU, contributing to efforts to optimize ICI treatment across the common cancers.

Methods: I will have the opportunity to progress a piece of translational work allied to the REFINE trial (REduced Frequency ImmuNe ChEckpoint inhibition) that is currently in set up and due to open to recruitment by the end of 2021. This will allow us to better understand the pharmacokinetic aspects of extending the interval between ICI treatment in responding patients. REFINE is one of a number of trials testing reduced treatment in cancer, a concept that is naturally challenging to the public and participants within clinical trials. A second strand of my research will work with the PPI groups on these studies, developing common themes and approaches for trials that will ensure optimized questions and recruitment alike. Finally there are a number of academic and commercial studies testing adding ICI to radical treamtent (including the IMPART project at MRC CTU). Through a basket approach I will collaborate with the methodology and meta-analysis groups at MRC CTU to identify the shortest duration of ICI likely to generate the maximal benefit in this situation.

How the results of this research will be used: The outcome from these three strands of work, in the context of internationally relevant studies will contribute meaningfully to global cancer care. Furthermore in being exposed to three different areas of work allied to clinical trials I will learn a huge amount in an exceptional environment and fulfill the requirements for a rewarding and high quality PhD


Research Activity Codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health Categories: CANCER AND NEOPLASMS
Award Title: Organisation and activation mechanism of AMPA glutamate receptor complexes
Funder: Wellcome Trust

Abstract: AMPA receptor (AMPAR) operation underlies learning, while receptor malfunction is associated with various diseases. Their uniquely versatile signalling arises from numerous auxiliary subunits that assemble into functionally diverse receptor super-complexes. The combination and stoichiometry of these components, and how they shape neuronal response properties, remains a central open question.We will elucidate the pathways leading to activation of a predominant AMPAR, building on our cryo-EM structures of this receptor, associated with two structurally diverse auxiliary subunits. Using cryo-EM, MD simulations and single-channel recordings, we will assess the differential contribution of core- and auxiliary subunits to the receptor’s characteristic activation time course.We will also investigate the mechanism of leading neurotherapeutics on gating, capitalising on our AMPAR structures associated with these ligands, and study the role of the receptor’s lipid environment through reconstitution into liposomes. We will complement these studies with time-resolved cryo-EM of gating intermediates, and structures of native AMPAR complexes, isolated from mammalian synapses.These experiments will uncover the principles underlying AMPAR organisation and activation. We will derive a comprehensive kinetic model, delineating how activation is modulated by auxiliary subunits, lipids and neurotherapeutics. Elucidating the conformational states selectively targeted by these ligands will facilitate targeted structure-based drug design.

Lay Abstract: AMPA receptor signaling underlies information processing, while receptor malfunction leads to various brain disorders, rendering them strategic drug targets. The activation of an individual receptor - the process leading to opening of the channel’s pore in response to agonist binding - involves multiple conformational transitions. Their rates and energies determine how the receptor processes information. Activation is modulated by auxiliary proteins that are expressed in region-specific patterns, and by drugs selectively targeting AMPAR subtypes. We will use cryo-EM and high-resolution single channel recordings to study activation of a predominant forebrain AMPAR complex. We will elucidate the modulatory mechanism of two major auxiliary subunits, and of leading AMPAR therapeutics in this process. We will generate cryo-EM structures of activation intermediates and of native AMPAR complexes derived from neuronal synapses. Together, we will lay the framework to understanding the fundamentals underlying synaptic communication and the action of selective neurotherapeutics in this process.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Award Title: Our Health, Our Voices. Engaging underserved audiences in health research.
Funder: Wellcome Trust

Abstract: “A diverse and inclusive public involvement community is essential if research is relevant to population needs and provides better health outcomes for all” (NIHR).
 
 
 
Situated in the heart of a vibrant NHS and University research environment, a diverse patient population and communities with some of the poorest health outcomes in England, our team will deliver a 5 year programme of exceptional engagement, within the context of Greater Manchester’s devolved healthcare system.
 
 
 
Based on our track record, knowledge and strengths, we will boldly experiment, learn from and reflect on, methods of working with people that address issues of social justice in health research. Our locally embedded long-term programme of activities will combine
 
 • Research-driven, arts-led approaches focusing on particular groups and scaled up to national audiences
 • Listening, responsive and relationship projects
 • Support for researchers and development of young and diverse engagement talent
 • Celebrating our communities who drive research
 • Sharing our learning far and wide, including through income generation methods
 
Thus generating more informed and inclusive health research, and people supported to learn, question, and enabled to actively contribute to such research.
 
 
 
Underpinned by significant organisational changes, including the launch of new business model maintaining our not-for-profit status, a communications overhaul, income generation and more efficient processes, we will enhance our reputation as pioneers in our sector, influencing positive change in people, research and practice.
 
 
 
Ultimately, we aim to be recognised as an innovative centre for excellence in engaged health research, and a leading practitioner in the UK working with underserved audiences.

Lay Abstract: No Data Entered

Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Overcoming immunomodulatory drug resistance in myeloma
Funder: Cancer Research UK

Abstract: Background:
The plasma cell malignancy multiple myeloma remains incurable despite advances in therapy. Immunomodulatory drugs (IMiDs) are the backbone of standard and experimental combination therapies at all stages of disease. IMiDs bind to the CUL4 E3-ubiquitin ligase, cereblon, leading to the degradation of neosubstrates including Ikaros and Aiolos, mediating their downstream effects which include decreased expression of the B-cell transcription factor IRF4. Acquired resistance following exposure to IMiDs has been associated with decreased protein and mRNA expression of cereblon. No significant recurrent mutations have been identified in cereblon suggesting a transcriptional, e.g. epigenetic, mechanism may underlie acquired resistance. Mechanisms underlying intrinsic resistance are poorly understood but are not related to differences in Ikaros and Aiolos degradation or cereblon expression. 

Aims:
I aim to identify and target the mechanism by which expression of cereblon is decreased in acquired IMiD resistance and which maintains cell proliferation, despite Ikaros and Aiolos degradation, in intrinsic IMiD resistance. I then aim to investigate the association of IRF4 mutations with outcomes in IMiD treated myeloma patients in order to uncover new insights into the biology of IMiD response. Finally, I aim to identify novel cereblon-binding compounds able to overcome intrinsic and acquired resistance and use these as tools to further explore mechanisms underlying IMiD resistance.

Methods:
Cell lines with acquired resistance to IMiD compounds have been generated and the DNA and histone methylation profile at the cereblon promoter will be studied to identify differences that may account for altered cereblon expression. Intrinsic resistance will be studied by analysing patient samples incubated ex-vivo with IMiDs prior to analysis. I will use proteomics to identify differences in neosubstrate degradation and RNA-seq to identify gene expression changes between sensitive and resistant patients. The downstream effects of IRF4 will be studied including the impact of the recurrent p.K123R IRF4 mutation. Isogenic cell lines with this mutation will be generated using PITCh-guided CRISPR and the effect on cell proliferation, gene expression and IMiD response examined. Finally, novel cereblon binding compounds will be screened to identify those able to overcome intrinsic and/or acquired resistance. Analysis of the differences in neosubstrate degradation that can overcome resistance will further inform our understanding of the mechanisms of IMiD resistance.

Impact:
The results of this research will further our understanding of IMiD resistant and refractory states, imperative to help identify pathways to target with novel therapeutics or combinations in order to improve patient outcomes.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS