NIHRDataInsights/HRCSData huggingface dataset:
Title: Tailoring health policies to improve outcomes using machine learning, causal inference and operations research methods
Funder: Medical Research Council

Abstract: To maximise the impact of health policies, policy evaluations need to go beyond the average effects and consider treatment effect heterogeneity. Recently, machine learning approaches have been proposed to estimate treatment effect heterogeneity in a flexible yet principled way, combined with rigorous causal inference approaches. These methods have been further extended to examine which individuals should be targeted by a policy, based on their observed characteristics (optimal treatment regimes). However, these methods have not yet been translated to the challenging context of the evaluation of large-scale health policies. Here, due to non-experimental evaluation designs, researchers need to adjust for observed and unobserved confounding, and to inform real-world policy making, there is a need to estimate interpretable health policy assignment rules, to account for budgetary and equity constraints, and to consider the long term costs and benefits of a health policy. To address these challenges, we plan to first compare combined causal inference/machine learning approaches to estimate heterogeneous treatment effects for subgroups and (conditional) individual level treatment effects. The methods will be extended to adjust for confounding in quasi-experimental studies, and we will test their performance by applying them in a case study and in a simulation study. Building on this work, we develop a framework that can answer the overarching question: which subgroups of individuals or communities should be 'treated' to maximise the health policy maker's objective function, subject to constraints? Third, to consider the full health benefits and costs of a policy, we combine with the above framework the tools of decision modelling. Outputs from this project will equip researchers with advanced tools to generate impact evaluation evidence that can inform the design of efficient health policies to promote population health and health equity objectives.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Dynamic regulation of chromatin loops by cohesins and CTCF in real time: physiology and pathology
Funder: Medical Research Council

Abstract: Chromatin loops represent basic units of genome organisation. The formation of a chromatin loop relies on cohesins and the CCCTC-binding factor (CTCF). The 4C and Hi-C analyses revealed formation of chromatin loops genome-wide. However, it is still unclear how the conformations of individual chromatin loops change over time and what molecular mechanisms drive such changes. We will visualize conformation of chromatin loops and observe their dynamic changes in real-time imaging of human cells. For this, we will select repetitive DNA sequences adjacent to two CTCF binding sites involved in loop formation and visualise them using nuclease-deficient Cas9 and single guide RNAs. Our pilot experiments show that this method is feasible and we will further develop and optimise it. Using the above method, we will investigate the formation rate and lifetime of chromatin loops. We will also study molecular mechanisms regulating their formation and dissolution. Based on these analyses, we will develop mathematical models for loop formation and dissolution. These analyses will establish an important framework for the real-time dynamics of chromatin loops. Meanwhile, cohesins facilitate both chromatin-loop formation and sister chromatid cohesion at CTCF-binding sites. However it is unknown how cohesins interlink two roles at the same chromosome sites - we will address this question. Mutations of cohesins and their regulators cause various congenital disorders and promote specific types of cancers. It is suspected that these mutations impair chromosome organisation, leading to such diseases. However, the specific mechanisms by which defects of cohesins and their regulators lead to these diseases are unknown. To obtain insight into such mechanisms, we will study how these mutations affect the dynamics of chromatin loops. In particular, we will focus on NIPBL haplo-insufficiency, which causes a congenital disorder, and STAG2 mutations, which are frequently found in cancers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Deciphering mechanisms of epigenetic regulation in Trypanosoma brucei, an evolutionarily distinct human pathogen.
Funder: Medical Research Council

Abstract: Molecular understanding of the role of distinct chromatin types in gene regulation, & the activities involved, are most advanced in mainstream eukaryotes (ie animals, yeasts) that represent only one eukaryotic super-group. However, distinct early-branching lineages have highly divergent histones & chromatin modifiers - histone post-translational modification writers, readers & erasers. An excellent example are trypanosomes, human parasites which use distinct machinery to interpret their genome. Currently, our understanding of trypanosome chromatin modifications & modifiers is rudimentary - few have been characterised. Our preliminary systematic analysis of putative trypanosome chromatin modifiers showed that several are enriched at RNAPII promoters including a putative histone methyltransferase Set27 and Chromo-domain partner protein. Surprisingly, none of the many chromatin modifiers we examined coat silent gene regions or repetitive elements that were expected to assemble distinct types of chromatin. This included the silent telomeric variant surface glycoprotein (VSG) genes that allow trypanosomes to evade human host immunity. However, the expression of synthetic TALE proteins designed to bind telomeric repeats identified two zinc-finger RNA binding proteins enriched in telomeric chromatin. This proposal addresses three questions concerning epigenetic regulation in trypanosomes: 1. How do putative histone writers and readers congregate at RNAPII promoters? 2. What is the role of zinc-finger RNA binding proteins in gene silencing at telomeres? 3. What is the composition and function of chromatin formed over silent VSG genes & repetitive elements? These studies will provide understanding of the mechanisms by which specific chromatin modifiers influence gene expression & heterochromatin formation in Trypanosoma brucei & related human pathogens. Key divergent chromatin modifiers have the potential to be exploited as novel parasite specific therapeutic targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Collaborative Computational Project for Electron cryo-Microscopy (CCP-EM): 2021 - 2026
Funder: Medical Research Council

Abstract: The CCP-EM partnership exists to further strengthen and expand the cryo-EM community. Activities can be broadly divided into three areas: (1) development of the CCP-EM software suite, (2) training programme and community events, and (3) strategic initiatives and outreach. We request funding for a core team of computational scientists to coordinate and develop these activities. Since software development, training and outreach are closely linked, we expect the team to work together in all areas. The software suite is designed to integrate individual programs from diverse sources into a convenient package for scientists. It provides a framework for collaborating with other developers and helping to make novel methods available to the community. Collaboration is required, and the suite is not intended to be a container for all available software. The core team is developing a set of Python libraries covering a data model, job control, scheduling and workflow definition, which will merge the RELION pipeliner and the existing CCP-EM project manager. We propose to continue this development, integrate it into the production version of RELION, and expand its use to the rest of CCP-EM, facilitating closer integration between reconstruction, model building and data validation. The extended framework will be used to integrate subtomogram averaging functionality, and develop the link to tomographic reconstruction. We will also develop on-the-fly processing for eBIC (and other facilities), tools for validation and simplified EMDB deposition, automation of data processing workflows and a new combined GUI for CCP-EM and RELION, as well as allowing third-party plugins to be easily incorporated into the pipeline. Machine-learning methods for data-driven analysis will be embedded at all levels. We will continue to organise the annual Spring Symposium, expand the training programme, contribute to international meetings, and organise hackathons for developers.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: The collaborative computational project for NMR (CCPN): supporting biological NMR for the biosciences, medicine and industry.
Funder: Medical Research Council

Abstract: CCPN has developed a graphics-based, adaptable and easy extendable NMR data analysis software platform for users which covers all aspects of biological NMR, including small molecule applications in NMR-based metabolomics and NMR-based screening. Our efforts are focused on easy spectrum visualisation and interpretation, smart tools for data analysis, NMR-based structure calculation and validation. This MRC partnership proposal aims to continue, enhance and advance the application of NMR in the biomolecular sciences through the development of novel tools, technologies and methodologies, knowledge sharing and exchange, as well as training and support with a particular focus on early career researchers. It builds on 20 very successful years and CCPNs undisputed crucial and greatly valued role in the biological NMR community. CCPN aims to foster collaborations and to represent the community in all relevant matters related to research funding and development of (research) policies. CCPN achieves its goals by working with all stakeholders. Specifically, the efforts of CCPN and its partners during the next 5 years will be directed to the following areas: 1. Development of software relevant for NMR 2. NMR in support of Biological Sciences 3. NMR in support of Medicine 4. NMR in support of Industry and 5. Outreach and training. With the current proposal we establish a long-term vision and extended approach in nurturing the collaborations with crucial current and new partners, extending the scope of the project and confronting numerous interesting, yet challenging future issues. The latter include automation and smart AI-inspired tools, the relationship between NMR, dynamics and molecular modelling approaches, data exchange, and RDM. The efforts of CCPN and its partners will be crucial to support the NMR biomolecular scientists in tackling many of the 21st century scientific challenges in our understanding of disease and the development of personalised medicine.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Coordinating the remodelling of cell polarity to form a functional organ.
Funder: Medical Research Council

Abstract: The objective of this new research grant is to elucidate how polarised tissue organisation arises from the collective action of individual cells. While a small set of conserved cell-intrinsic polarity regulators has been identified through genetic studies across a range of systems, we do not yet have a good understanding of the general logic by which these proteins break cellular symmetry to polarise an entire cell. Nor do we understand how this information is combined with extrinsic cues, both soluble and mechanical, to coordinate the formation of a complex 3D multicellular tissue during development. The developing fly eye is one of the best systems to study this in a living animal. Building upon unexpected findings in our laboratory that alternative mechanisms control polarity in different retinal epithelial cell types, we will reveal i) the different pathways by which polarity is induced in individual cells, and ii) how interactions between cells coordinate this polarity across a tissue in space and time. We expect that the principles we uncover will be of general importance, since cell polarity is critical for epithelia to function as selective barriers that mediate exchange between the outside and inside of an organism. By focusing on a genetically tractable, physiological animal model system of organogenesis, this proposal aims to elucidate how polarity machineries working within cells and communication between cell types come together to induce the functional polarised organisation of complex animal tissues, in health and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: How do 'effects' differ across time? Understanding health inequalities by triangulating across multiple data sources and empirical strategies
Funder: Medical Research Council

Abstract: The recently purported causal and DNA 'revolutions' in science have largely focused on establishing the presence or absence of causal effects; yet causal effects related to societal factors are likely to differ across time. This project seeks to address this, by evaluating how the effects of socioeconomic, cognitive and genetic factors on health have changed across time - both year of birth (1946 to 2001) and age (maximal span: infancy to old age). This will also provide evidence on key unresolved issues relating to causality in health inequalities. This is a secondary data analysis project, consisting of the below objectives: Objective 1: Evaluate whether the effects of socioeconomic position on health outcomes have changed across time. Objective 2: Evaluate whether the effects of cognition capability on health outcomes have changed across time. Objective 3: Evaluate whether the effects of common genetic variants on health outcomes have changed across time. The empirical approach will triangulate across multiple data sources and analytical approaches in order to provide robust evidence. Multiple cross-sectional and longitudinal datasets will first be used to examine change across time in socioeconomic inequalities in health outcomes (body mass index, blood pressure, and mental health - depression and anxiety spectra); this will advance knowledge of descriptive change in health inequality. A range of longitudinal studies will then be used to investigate causal effects of socioeconomic, cognitive and genetic factors on health outcomes. These include the UK birth cohort studies, initiated in 1946, 1958, 1970, 1991, and 2001, and a large Norwegian study (HUNT). Multiple approaches to causal estimation will be used - using observed life course data, and genetic data (including use of Mendelian Randomisation). This will provide new knowledge on how causal effects may change across time.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Intervention development for community-based self-referred social prescribing
Funder: Medical Research Council

Abstract: The linking of individuals to social interventions outside of NHS healthcare for health and wellbeing, social prescribing or SP, is the current zeitgeist in UK health policy. There is a financial commitment for every GP practice to have access to a SP link-worker by 2023 and there are 1,000 more SP staff being recruited as of early 2020. Most current literature relates to primary-care focused programmes and, we feel there an opportunity to work with stakeholders to develop a formal route for self-referrals into community-based activities for health. This would reduce the use of the health service "scaffolding" and help to build healthier populations through prevention. We will use an intervention development methodology informed by systems science. We are partnering with SIPHER (Systems Science in Public Health and Health Economics Research), to develop social prescribing system maps. We will generate a detailed understanding of how SP currently works alongside qualitative insight into what works in terms of connecting people to the services they need. We propose two phases. Firstly, evidence synthesis building on our previous work to map provision. Secondly, consultation meetings and focus groups to establish current pathways and activities, as well as different contexts. We will aim to better understand the ways in which systems are currently brought together and the barriers to pathways from the individual perspective. We will bring this work together through the development of a detailed systems map explicating the core relationships. We will also provide programme theory describing the relationships between the actors, systems and resources needed, and surfacing the underlying assumptions and contexts in which pathways can operate best. Together, these will form the basis for guidance for a whole systems approach to social prescribing and our next step will be to seek funding to test the systems map and pathways developed here using primary data.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: MR/V005405/1
Funder: Medical Research Council

Abstract: Spermatogonial stem cell (SSC) transplantation promises a wealth of applications, from restoration of fertility in cancer patients, to the preservation of genetic diversity of farm animals and endangered species. Yet, low transplantation/engraftment efficiencies make it currently unviable as a practical technology. Using a combination of lineage tracing and intravital imaging, our previous studies have resolved the functional identity and fate behaviour of SSCs in mouse testes, both during homeostasis and regeneration following injury. These studies have shown that SSCs are highly heterogeneous, transitioning reversibly between states biased for renewal and poised (licenced) for differentiation. Moreover, states that have entered into a differentiation pathway can reacquire renewal potential in response to injury, greatly increasing the size of the effective stem cell pool. Yet, despite a predictive understanding of cell dynamics, the regulatory programmes remain in question. Here, by delineating the mechanisms that regulate stochastic renewal and cell state flexibility, we aim to identify compounds that can modulate cell fate choices and increase transplantation efficiency, unlocking the potential of this technology. To develop this programme, we will exploit advances in single-cell technologies (scRNA-seq and scATAC-seq) to resolve the transcriptional heterogeneity of SSCs and their progenies during steady-state and regeneration. By combining these approaches with in vivo tracing, we will use comparative genomics to identify the pathways that control fate asymmetry. As a step towards clinical application, we will mine human data and perform deep-phenotypical characterisations of human SSCs using a multiplex proteomics approach to compare the activity of signalling pathways in mouse and human testes. These insights will allow us to identify and test chemical modulators, with the aim of increasing SSC regeneration capability and transplantation efficiency.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: STRUCTURE-INFORMED STUDIES OF THE EXTRACELLULAR REGION OF THE HUMAN NOTCH RECEPTOR IN HEALTH & DISEASE
Funder: Medical Research Council

Abstract: Understanding the molecular basis of Notch signaling is of significant biomedical importance. Despite the identification of the Notch receptor more than 30 years ago, we lack a description of its full structure, which is crucial for understanding how it functions at the cell surface. This major conceptual gap will be addressed by analyzing the structure and dynamics of an important region in its extracellular domain. Our previous work established a structural model of EGF4-13. Strikingly, we observed that the receptor does not simply extend from the cell-surface, but has the potential to adopt a range of dynamic conformations. We now aim to address the structure and function of EGF20-27 and the region that links this to the ligand-binding region (LBR) studied previously. A multidisciplinary approach will be taken: 1. To study the structure & dynamics of a range of EGF domain fragments from the EGF14-27 region of the Notch receptor using mainly NMR spectroscopy, calcium-binding measurements & SAXS to define the overall architecture of this critical region. 2. To further characterise the binding interface of the Ax/EGF11-13 (LBR) interaction using site-directed mutagenesis and established FACS and ELISA-type assays, to determine if it confers an intramolecular hairpin loop structure to Notch and whether or not ligand competes with Ax. 3. To perform Notch activation experiments in cells utilizing structure-informed site-directed mutants of full-length Notch and purified or cell-surface-expressed ligands to test the functional importance of the Ax/LBR pairwise interaction and EGF domain interface rigidity/flexibility for activity. These data will enable us to understand the cell-surface architecture of Notch from EGF4 to EGF27, inform on the biological significance of the Ax/LBR interaction for structure and function, and give new insights into the molecular basis of activatory and inhibitory Notch complexes at the cell surface.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Targeting the cellular metabolism to treat tissue-specific mitochondrial diseases
Funder: Medical Research Council

Abstract: Although mitochondria are present in almost all eukaryotic cell types, mitochondrial diseases have distinct tissue-specific phenotypes that are poorly understood. Our project focuses on mitochondrial diseases characterised by impaired mitochondrial translation, which can be caused either by mtDNA mutations (often in mt-tRNAs) or in nuclear encoded proteins that play a role in mitochondrial translation. Mt-tRNA or nuclear gene mutations affect tRNA levels and structure directly or indirectly, leading to a defect of mitochondrial protein synthesis. These mutations can also lead to the presence of free tRNAs without their cognate amino acid ('uncharged tRNA'), which constitutes a stress signal for cells. We will investigate whether different tissues have different levels of uncharged tRNAs and whether this correlates with the vulnerability for mitochondrial defects. Uncharged tRNA activates the integrated stress response (ISR), a major signalling pathway that allows eukaryotic cells to sense stress and adapt to it. We obtained fibroblasts from patients with different mitochondrial translation defects to determine tRNA and ISR levels. We will reprogram the fibroblasts to iPSCs and differentiate those to neurons, muscle cells and cardiomyocytes. Next, we will examine what metabolic changes are induced by the activated ISR in these cells. In one disease studied by our laboratory, reversible infantile respiratory chain deficiency (RIRCD), the metabolic changes induced by the ISR in the muscle of patients allowed a recovery of the patients from severe disease. Our results indicate that the ISR is protective to some cells and damaging to others. We would like to exploit the knowledge gained in RIRCD to induce similar metabolic changes in mitochondrial conditions that are currently not reversible. Modifying the ISR or manipulating key metabolic factors (amino acids, FGF21) may enable us to devise therapeutic options for mitochondrial translation defects in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE