NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Understanding the multicellular dynamics of clear cell renal cell carcinoma from initiation to the response to systemic therapy
Funder: Cancer Research UK

Abstract: Background
Half of all patients diagnosed with clear cell renal cell carcinoma (ccRCC) will succumb to the disease. This is despite the extremely long latency period with the first mutation acquired many decades prior to diagnosis. As a surgeon, I am particularly motivated to help improve the risk stratification and direct therapy for those patients who appear to present with localised disease only to relapse with metastasis after surgical resection.

Aims
This research proposal aims to discover the functional dynamics of ccRCC; from the initiating events, to small renal masses, through to higher risk tumours and their response to systemic therapy. I will also seek to understand the functional heterogeneity in the multi-cellular microenvironment of a range of ccRCCs, focussing on the differences between high-risk and low risk disease.

Methods
The transforming events that underpin the development of clear cell renal cell carcinoma will be quantified through the functional interrogation of early cancer cell clusters and the non-cancerous at risk cell population with chromosome 3p loss.
Multiregional single cell RNA sequencing with bulk whole exome sequencing of low versus high risk renal cell carcinomas will allow us to chart the functional changes throughout a tumour’s evolution and delineate the trajectory from indolence to metastasis.
These methods will also be applied to patients undergoing neo-adjuvant therapy, comparing the single cellular function microenvironment from pre-treatment biopsies and post-treatment nephrectomy specimens.

How the results of this research will be used
Understanding initiating events may inform possible preventative strategies, particularly for those patients with familial renal cancer in whom the penetrance of cancer approached 80%.
The discovery of key functional differences between high and low risk disease will aid the applicability of molecular based decision making to help reduce the incidence of relapsed disease following surgery with curative intent.
Examining the response to systemic therapy will help aid our understanding of tumour sensitivity or resistance, paving the way for intelligent design of combinatorial treatments.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Understanding the psychological risk factors for believing political misinformation by merging neural network and multiple regression models.
Funder: The British Academy

Abstract: In the last few years, work has begun to diagnose the individual risk factors associated with believing political misinformation. However, many of these factors have been considered in isolation. Since many psychological factors covary, it is vital to understand which factors predict vulnerability to misinformation above and beyond other factors. Historic techniques for evaluating the most important predictors in a dataset have some limitations. Multiple regression is prone to overfitting, reducing the likelihood of replicability. Machine learning techniques (i.e. neural networks) are criticized for their lack of transparency. This work will use state-of-the-art techniques to merge the outputs of neural networks and multiple regressions to better understand the combination of features which best predict vulnerability to misinformation. This project will find a model with the (out-of-sample) predictive power of a neural network and the transparency of a multiple regression model.


Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: GENERIC HEALTH RELEVANCE;MENTAL HEALTH
Award Title: Understanding the relationship between depression and trajectories of physical multimorbidity accrual: longitudinal analysis of UK Biobank data
Funder: Medical Research Council

Abstract: Importance and aim. Multimorbidity poses major challenges to researchers and to health systems. Physical condition-depression multimorbidity is particularly interesting because it is common, appears to have a bidirectional relationship, and is associated with worse outcomes. The aim of this study is to use UK Biobank data to identify trajectories of physical condition accrual in middle and older age, and examine how associations with depression at both baseline and follow-up.  In objective 1, we will build on our previous work to define which conditions we are going to count, and define trajectories of physical condition accrual in three ways: (1) Unweighted counts of number of conditions incident during follow-up; (2) Latent class trajectory modelling to classify patients in terms of the count trajectory, and; (3) Agglomerative hierarchical and k-means clustering to classify patients in terms of the types of conditions they accrue during follow-up. We will additionally define a number of measures of depression at both baseline and follow-up.  In objective 2, we will examine how baseline depression (and sociodemographic, lifestyle and risk factor characteristics) is associated with subsequent physical condition accrual using Poisson regression and multiple event survival analysis (outcome = condition count) and multinomial regression (outcomes = count trajectory and trajectory-by-condition-cluster cross-classification).  In objective 3, we will examine how physical condition accrual during follow-up is associated with subsequent incident and recurrent depression using logistic regression for multiple depression phenotypes. Outputs. The substantive findings will be of widespread interest, but the derived variables (individual morbidities, trajectories and condition clusters) and methods will also support future studies in Biobank using blood assay and genotype data, and implementation in other datasets.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Understanding the role of messenger RNA regulation in pain nerves during osteoarthritis
Funder: Versus Arthritis

Abstract: Hyperalgesia is a recognised feature of osteoarthritis which is at least in part due to changes in nociceptor neurons that innervate the joint. Regulation of local protein synthesis by mRNA localisation and cytoplasmic polyadenylation have recently been implicated in nociceptor plasticity. Indeed, we have shown that the polyadenylation inhibitor cordycepin affects pain behaviour in rodent models of osteoarthrits. There is as yet very little knowledge on which mRNAs are localised and polyadenylated  in nociceptor neurons and their role in hyperalgesia.

In this mulitdisciplinary PhD project, the student will use mRNA tagging, RNAseq and knockdown techniques to:

1)    Identify regulated mRNAs  in axons of nociceptors during pain signalling in culture system

2)    Determine the role of polyadenylation and translation regulation on nociceptor excitability in culture

3)    Investigate the role of mRNA regulation in pain signalling using an in vivo mouse model of osteoarthritis.  

4)    Identify nociceptor axon branch-specific mRNAs and their changes in a mouse model of osteoarthritis

 This work will improve our understanding of nociceptor function and aid the development of polyadenylation inhibitors as medicines for osteoarthritis pain. It will provide excellent training in advanced RNA biology, microfluidic culturing of neurons and animal models of osteoarthritis for a talented student.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: MUSCULOSKELETAL
Award Title: Understanding the structural basis of specificity in mitochondrial lipid transport and its role in drug resistance
Funder: Medical Research Council

Abstract: Mitochondrial membrane lipids are either imported from the endoplasmic reticulum (ER) or synthesized at the mitochondrial inner membrane from ER-derived precursor lipids. Recent studies have identified a conserved class of lipid transfer proteins in the intermembrane space, namely the Ups/PRELI family, which ensure intramitochondrial lipid distribution and synthesis by shuttling phospholipids between both mitochondrial membranes. Remarkably, they do this in a highly lipid-specific manner allowing defined alterations in the membrane lipid composition by regulated lipid transfer. Disturbances in the PRELI system play active roles in regulating apoptosis and driving drug resistance in cancer as well as being implicated in other human disease. The crystal structure of the phosphatidic acid transporter revealed some of the basic features of phospholipid recognition, but the basis for lipid specificity of Ups/PRELI proteins and the transport process remained enigmatic.  In this new proposal we will apply interdisciplinary approach to understand fully the mechanism of lipid transport and specificity within mitochondria. Advance structural biology methods together with gain-of-function genetic screens in yeast and biochemical assays will uncover the critical determinants that drive specific lipid transport.  This proposal will complete our understanding of the molecular mechanism of lipid transfer between mitochondrial membranes and how the lipid homeostasis of mitochondrial membranes is maintained.  Using our insight, we will also discover novel ways of manipulating the process, which will new ideas for treating dysregulation but are of broad relevance for other cellular lipid transport processes.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Understanding the unique properties of the Sin3A histone deacetylase complex in transcription and cell viability
Funder: Medical Research Council

Abstract: Histone deacetylase 1 and 2 (HDAC1/2) regulate global histone-acetylation levels as common components of four distinct multi-protein complexes: Sin3A, NuRD, CoREST and MiDAC. These complexes have definitive roles in all nuclear processes, including DNA repair, DNA synthesis and gene expression. Pan-HDAC inhibitors (HDACi) are used in the clinic to treat cancer and depression, although their use is associated with several debilitating side-effects. Our goal is to develop small-molecule inhibitors against each of the four HDAC1/2 complexes using a PROTAC approach, to understand their function in cells and develop novel therapeutics. PROTACs are small hetero-bifunctional molecules which incorporate a known binding moiety to the protein of interest (POI, e.g. an inhibitor), coupled to a ligand for an E3 ubiquitin ligase. Direct recruitment of the E3 ligase to the POI via the PROTAC, targets it for ubiquitination and ultimately degradation. As a proof-of-concept, we have tagged both alleles of Sin3A in embryonic stem cells (ESCs) with an FKBP12-F36V domain, so that it can be degraded by a known PROTAC, dTAG-13. Addition of dTAG-13 to the culture media results in loss of Sin3A protein within 2 hours and a loss of ESC viability by 72 hours. Loss of viability is unique to Sin3A among the range of HDAC1/2 complexes and we would like understand why, at molecular level. Using Sin3A-FKBP12-F36V cells, we now have the ability to address absolutely fundamental questions of Sin3A biology for the first time: (i) what are the direct transcriptional targets of Sin3A and how do these contribute to active transcription; (ii) understand the requirement for Sin3A/HDAC1 in DNA replication and genome stability; and (iii) define specific sites of Lys-acetylation regulated by Sin3A/HDAC1. Furthermore, by using a comprehensive range of deletion mutants we can identify the critical Sin3A domains (PAH1, HID, etc.), and protein-protein interactions they mediate, required for these activities.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Unravelling cancer stem cell heterogeneity in myeloproliferative neoplasms
Funder: Cancer Research UK

Abstract: Background    Intratumoural heterogeneity (ITH) underlies many of the challenges we face in cancer  medicine, including therapy-resistance, disease progression/evolution and relapse after  seemingly effective therapy. New techniques that resolve heterogeneity at the single-cell  level are ideally placed to unravel ITH and provide entirely new insights into cancer biology,  accelerating the development of new approaches to improve outcomes for patients. The  existence of rare cancer stem cells (CSCs) in certain tumours has important implications for  ITH, as it is ultimately CSCs that are the unit of evolution and selection by therapy. Arguably,  the best characterised CSC-propagated malignancies are chronic myeloid neoplasms, which  are excellent tractable disease models for cancer biology. The focus of this proposal is to  apply single-cell genomics to study ITH of CSCs in chronic myeloid neoplasms associated  with poor prognosis, high rates of clonal evolution and therapy-resistance.  Aims    To resolve CSC heterogeneity in paediatric myelodysplasia (PMDS), juvenile  myelomonocytic leukaemia (JMML) and U2AF1-mutant myeloproliferative neoplasms (MPN)  with the ultimate objective of improving precision medicine and therapeutic/biomarker  discovery.    Methods    PMDS: We will analyse PMDS haematopoietic stem and progenitor cells (HSPCs) pre- and  post-allogeneic transplantation using high-throughput single-cell RNA-seq (scRNA-seq)  combined with a novel method for combined scRNA-seq and mutation analysis we  developed (TARGET-seq). Analysis of serial samples will identify HSPC/CSC  subpopulations associated with therapy-resistance. Presence of novel HSPC/CSC  subpopulations will be correlated with clinical characteristics, follow-up data and laboratory  findings to classify patients into distinct disease groups. Identification of CSC subpopulations  that predict disease relapse/progression (including after AHSCT) will facilitate  therapeutic/biomarker discovery.    U2AF1-mutant MPN: We will apply TARGET-seq to analyse HSPCs from a cohort of  patients with U2AF1-mutant MPN. Understanding the mechanisms by which such mutation  exert clonal dominance in human HSPCs is restricted by the marked heterogeneity found in  this compartment, including mRNA-splicing heterogeneity caused by the U2AF1-  spliceosome mutation itself.    We will combine this large-scale scRNA-seq analysis with state-of-the-art molecular biology  and stem-cell assays to identify and validate candidate biomarkers and therapeutic targets,  including immunotherapy targets.    Potential impact of this research      The most tangible impact of this work on patient outcomes is likely to come from better  approaches to diagnose, monitor (biomarkers of early relapse) and treat patients with PMDS  and MPN.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Unravelling signatures of clonal response, resistance and evolution of high-risk essential thrombocythaemia at single-cell resolution
Funder: Medical Research Council

Abstract: Single-cell genomics techniques have enormous potential to resolve intratumoural heterogeneity, of importance for precision medicine in cancer. However, translating this powerful new technology through to direct clinical application requires evidence that such an approach might benefit patients in specific disease area. The overarching aim of this research is to provide this proof of principle of the clinical utility of single-cell genomic analysis in a disease with an unmet need: high-risk essential thrombocythaemia (ET). We hypothesise that single-cell analysis of haematopoietic stem and progenitor cells (HSPCs) in hydroxycarbamide-resistant/intolerant ET patients in the MAJIC study will reveal considerable heterogeneity reflecting distinct molecular signatures, not detected by mutation screening of bulk cell populations, and will therefore facilitate the identification of novel biomarkers and therapeutic targets. We will use a novel technique developed in the Mead laboratory (TARGET-seq) to carry out this analysis. This technique allows ultrasensitive mutation analysis (with allelic dropout rates <3%) combined with unbiased whole transcriptome analysis of the same cell. No currently published method allows this combined analysis and we believe that this will prove to be an extremely powerful method for precision medicine. The technique also allows identification on non-clonal HSPCs to provide insights into cell-extrinsic disruption in the bone marrow microenvironment in high-risk ET. I am committed to a career as an academic haematologist and am excited about the potential application of single-cell genomics technologies in clinical medicine. This innovative technology is likely to move towards wider clinical application in the coming years and I anticipate that the state-of-the-art training in this field that I will receive, as described in this proposal, will set the foundation for a career as a clinician scientist working in this exciting area of research.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: BLOOD;GENERIC HEALTH RELEVANCE
Award Title: Unsilencing Sexualised Torture: Identifying and Responding to Sexual Torture Amongst Refugee Survivors of Torture
Funder: The British Academy

Abstract: Torture is a serious violation of human dignity, but one which remains peripheral to mainstream sociology, often situated instead in psychological studies or international relations. Sexual torture, and sexualised torturous violence (Canning, 2016), is further silenced in all realms of study, in part due to the complexity in identifying or defining what sexual constitutes sexual torture, and in part due to social silencing inherent to the shame and stigma associated with sexual violence more broadly. Using narrative oriented inquiry of 10% of a 1500 case dataset of survivors of torture (n = 150) based at the Danish Institute Against Torture, and focus groups with practitioners, this study aims to: explore documentation of sexualised violence amongst torture survivors; develop an epidemiological dataset on forms of violence inflicted, who by, where (spatially and geographically) and when; and how best to name, respond and address sexual torture amongst survivors of torture generally.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: DISPUTED AETIOLOGY AND OTHER
Award Title: Untangling gene regulatory networks controlling host-pathogen interactions of the antimicrobial-resistant human pathogen Klebsiella pneumoniae
Funder: Medical Research Council

Abstract: Klebsiella pneumoniae (Kp) is an important cause of nosocomial and community-acquired infections. Treatment is hindered by the global spread of multidrug-resistant strains, and of special concern are carbapenem-resistant isolates of sequence type ST258. Although Kp is well-characterised from a genomic perspective, our knowledge of the molecular mechanisms underpinning its pathogenicity is still limited. Our aim is to define these mechanisms underpinning Kp infections of eukaryotic immune cells through four complementary work packages. WP 1 will simultaneously profile the transcriptome of ST258 isolate RH201207 during macrophage infection and of the host in response by dual RNA-seq. WP 2 will reconstruct the gene regulatory networks responsible for the transcriptional responses of Kp to macrophage invasion using the complementary functional genomics approaches of ChIP-seq and TraDISort. It will be possible to fully determine the upstream and downstream regulatory pathways of key regulators and reconstruct the complete transcriptional networks. WP 3 will identify the transcriptomic changes under infection-relevant conditions to compare RH201207 to other pathogens such as S. Typhimurium and E. coli as well as a previously published Kp strain. WP 4 will examine the diversity of host interaction within large collections of fully sequenced clinical Kp isolates by analysing their capacity to replicate inside macrophages using fluorescence dilution. This will allow us to perform exploratory genome wide association studies to test the association of mutations and the gene presence between each variant and the potential for intramacrophage replication. The knowledge gained has great potential to establish broadly applicable technologies for studies of bacterial gene regulation networks, identify genes necessary to infect and manipulate host cells which could act as novel antibacterial and antivirulence drug targets and discover pathways of the immune response to Kp exposure


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Untangling the mechanistic links between heart and brain health in older populations: An AI assisted toolkit for assessing dementia risk
Funder: Medical Research Council

Abstract: Dementia is a global public health priority. There is abundant evidence of a strong association between cardiovascular diseases (CVD) and associated risk factors (e.g. hypertension) with dementia risk. Yet, knowledge of the mechanistic pathways linking CVD and brain health is limited. Further, there is a lack of screening instruments to reliably assess risk of dementia and suggest possible interventions for further study. To date, dementia treatment, prevention and risk reduction trials have shown limited success. This is largely due to inadequate knowledge of the disease pathways underlying dementia. Therefore, using Artificial Intelligence (AI) methods synthesising clinical, lifestyle, and socio-demographic data from the Cohort Studies of Memory in an International Consortium (COSMIC), the Emerging Risk Factors Collaboration (ERFC), and UK Biobank, we aim to develop, in people with CVD, novel models for predicting the risk of (1) incident dementia; and (2) dementia-related mortality.  The project will be completed in two phases. The first (Months 1-5) will involve secondary data analysis. The aim will be to develop and incorporate novel techniques for advanced analytics, including machine learning architectures, to enhance knowledge regarding correlations between dementia and CVD to establish a better patient-centric disease prediction methodology. We will answer questions like: What are the disadvantages and limitations of current approaches to calculate risk; what are the most important factors driving risk for a particular individual or data cohort; and, how can we incorporate knowledge domain to improve predictions? The second (Month 6) involves dissemination including knowledge sharing and design of a full application focused on translating the models into electronic toolkits. The timing of the study is critical as new approaches are needed to accelerate the development and delivery of precision interventions for dementia risk reduction and prevention.


Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.1 INDIVIDUAL CARE NEEDS
Health Categories: CARDIOVASCULAR;NEUROLOGICAL