NIHRDataInsights/HRCSData huggingface dataset:
Title: The ChEMBL database
Funder: Wellcome Trust

Abstract: Drug discovery is a very challenging and expensive activity with a low success rate. Access to relevant, quality data is critical to enable the success of drug discovery projects which will deliver the new medicines that address unmet medical need. Large collections of data are also key to improving the overall drug discovery process, for example by developing computational models or understanding the causes of attrition. Traditionally, only those working in large pharmaceutical companies have had access to significant amounts of drug discovery data. That situation changed dramatically in 2008 when the Trust funded the development of the ChEMBL database as an open-access, public repository of data on bioactive molecules. This proposal aims to build upon the success of ChEMBL as a key community resource, with further goals of expanding our data coverage; improving the organisation of our data to ensure full FAIR compliance including improved disease annotations; enhanced data access via our web interface, workflows and tools; and improved sustainability of our infrastructure including a streamlined release process and open source software tools.

Lay abstract: The discovery of new medicines takes many years, significant financial investment, and the combined expertise of many scientists. Key to this is understanding the activity and properties of drug-like molecules. ChEMBL provides a free and open access database for the wider scientific community to obtain and analyse data that would otherwise be buried within the scientific literature. ChEMBL contains a large collection of data on how drugs and other bioactive molecules interact with biological systems. Within this project we aim to increase the amount and types of data contained within the database and enhance our annotations of that data to enable users to pose ever-more sophisticated queries. This, coupled with major improvements to our website and to the underlying computational processes, will enable drug discovery scientists to be even more effective in their quest for new medicines.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: The Cellular and Physical Mechanisms of Developmental Symmetry
Funder: Wellcome Trust

Abstract: The formation and maintenance of bilateral symmetry of the vertebrate body is intimately related to developmental abnormalities such as scoliosis and neural tube defects. The body axis forms in the early embryo when multiple tissues undergo drastic morphogenesis. The mechanical forces and their underlying cellular dynamics that ensure body axis symmetry are poorly understood. I hypothesize that the paraxial mesoderm produces lateral compression on the axis to prevent it from bending. To test this hypothesis, we will image cell and tissue dynamics of body axis formation in chick embryos. Using this information, we will develop biophysical models that predict tissue forces. These models also allow theoretical assessment of the constraints and key parameters that control variability of symmetry. Using surgical ablations and molecular perturbations on different body axis tissues, we will analyze the cellular and tissue mechanisms of asymmetry response and correction. Using a novel device combining high-sensitivity cantilevers coupled with position control and live imaging, we will quantify and alter both forces and mechanical properties of different tissues. Together, these approaches will integrate quantitative maps of cell dynamics, tissue shapes and soft matter mechanics that are essentially a physical solution of body symmetry formation and morphogenesis in general.

Lay abstract: How a single cell becomes a functional individual is one of life's biggest mysteries. A sophisticated structure like the eye forms from a collection of tissues during the development of an embryo. These tissues grow and deform and interact with each other to construct an organ. The mechanical forces that the tissues create and experience during this process are poorly understood. This knowledge is important as it might explain how developmental defects take place and provide guidance for engineers to create replacement organs and tissues from stem cells. This proposed project studies the particular feature of body axis symmetry, namely the formation of a straight spine, in vertebrate embryos (including human). We aim at combining imaging, theory and biomechanics to identify the forces that straighten different tissues of the body as they grow, and to find the mechanisms that correct curvatures and the situations when such mechanisms fail.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Kinetochore–microtubule interactions: steps towards bi-orientation
Funder: Wellcome Trust

Abstract: To maintain genetic integrity, eukaryotic cells must properly segregate sister chromatids to opposite spindle poles during mitosis. This process has important medical relevance because chromosome mis-segregation plays causative roles in human diseases such as cancers and congenital disorders, which are often characterized by chromosome instability and aneuploidy. For proper chromosome segregation, it is vital to establish correct kinetochore–microtubule interaction in early mitosis, prior to segregation. We will investigate how kinetochores initially interact with microtubules on the mitotic spindle and how errors in kinetochore–microtubule interactions are resolved to establish correct interactions. In particular, we will address the following questions: A) What are the molecular mechanisms regulating the kinetochore–microtubule interface during early mitosis? B) What are the mechanisms resolving errors in kinetochore–microtubule interactions and stabilising correct interactions in a tension-dependent manner? To address evolutionarily conserved mechanisms, we use budding yeast as a model organism because, in this organism, a single microtubule attaches to a single kinetochore in metaphase – this considerably simplifies our analyses. We use methods in cell biology, molecular genetics, biochemistry and computer simulation, and address not only molecular mechanisms but also the biological significance of step-by-step development in the kinetochore–microtubule interaction.

Lay abstract: Human cells store their genetic information in 46 chromosomes. To maintain this vital genetic information, a complete set of chromosomes must be inherited precisely by each daughter cell after cell division. Errors in this process cause cell death and various human diseases, such as spontaneous miscarriage during pregnancy, genetic abnormalities and cancers. Our research goal is to understand the basic mechanisms that ensure accurate chromosome inheritance when cells divide. These mechanisms involve how chromosomes efficiently and correctly interact with a cellular apparatus called the mitotic spindle that subsequently moves chromosomes into the new daughter cells. To examine chromosome interactions with the mitotic spindle in fine detail, we will use advanced methods in cell biology, biochemistry, molecular genetics and computer simulation. The results of our research should contribute to understanding how various human diseases involving errors in chromosome inheritance arise, and how they might be prevented.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: TRANSCRIPTIONAL REGULATION OF SELF-RENEWAL IN HUMAN HAEMATOPOIETIC STEM CELLS
Funder: Wellcome Trust

Abstract: Generation of functional HSC from pluripotent cells and robust HSC expansion in culture are limited by our incomplete understanding of the self-renewal process. My goal is to unveil the regulatory pathways that sustain HSC self-renewal, based on modulation of gene expression at pre- (chromatin modification) and co-transcriptional (transcriptional elongation and RNA polymerase II pausing) levels and as directed by the metabolic state of the cell. I will carry out my scientific goals with the following aims: 1. Determine the regulation of HSC self-renewal though modulation of transcriptional rate and RNA polymerase II activity. 2. Understand the role of HSC metabolism and nutrient availability in the regulation of the HSC self-renewal gene regulation machinery. 3. Modulate HSC transcriptional regulation to achieve successful HSC generation in culture. These research avenues will lead to a better understanding of the molecular basis of self-renewal and will provide a foundation to improve the generation and expansion of engraftable human HSCs in culture, in order to fully exploit their potential for clinical applications. This work will expand our current knowledge of the HSC self-renewal process and provide new insights into the molecular features of stemness, with implications for other tissue stem cells and the cancer field.

Lay abstract: Haematopoietic stem cells (HSC) provide a lifelong supply of blood and immune cells. While they continuously produce specialised cells, they also replenish a pool of stem cells in the bone marrow, a property known as self-renewal. Thanks to this property, bone marrow or cord blood transplantation provide a life-saving treatment for blood and immune-related diseases. nonetheless, practical limitations, such as donor-matching or insufficient number of cells render these therapies unfeasible or unsuccessful for many patients. Attempts to overcome these limitations have been unable to create a reliable source of blood stem cells for patients, mostly because of defective self-renewal. My research will focus on understanding the mechanisms that allow human HSC to function through sustained self-renewal, as determined by the expression of specific set of genes that define HSC function. By gaining a better understanding of HSC biology, my studies will contribute to the development of successful novel HSC therapies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural mechanism of genome acetylation and 3D folding
Funder: Wellcome Trust

Abstract: Recent chromosome capture experiments have revealed a hierarchical 3D organisation of the genome ranging from Topologically Associating Domains (TADs) to larger-scale active, euchromatic and inactive, heterochromatic compartments. TADs arise through chromatin loop extrusion by cohesin/CTCF while compartments arise through epigenetic modification of the chromatin polymer. It has long been known that dynamic histone acetylation switches between repressive and permissive chromatin, a key event in transcriptional activation. We aim to capture cohesin in different structural states to understand how it is regulated and catalyses large-scale chromatin transactions. We also aim to understand the molecular mechanism behind acetylation-dependent activation of chromatin a reaction that is critical for the establishment of active euchromatin and may contribute to genome compartmentalisation and enhancer-promoter interaction. This proposal has the potential to transform our understanding the molecular mechanism behind two key reactions that contribute short- and long-range 3D genome architecture. It is possible that both mechanisms are interconnected and provide unifying principles to explain gene regulation with broad implications for health and disease.

Lay abstract: Chromosomes in our cells are folded in a precise manner to fit into the cell nucleus. Despite this compact folding, genes must be able to be switched on and off as required for normal cell function. Altering the structure of the compact DNA is necessary for gene activation and repression. One of the main regulators of the 3D genome architecture is cohesin, a ring shaped molecule. Using structural and functional analyses we will investigate how various accessory factors regulate cohesin function and 3D genome folding. In addition, we will investigate how DNA sequence-specific transcription factors bring chromatin modifying enzymes to particular positions in the genome to enable 3D genome folding and make these regions active. Our work has the potential to transform our understanding the molecular mechanism behind two key reactions that contribute short- and long-range 3D genome architecture and gene regulation.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The European Xenopus Resource Centre
Funder: Wellcome Trust

Abstract: Xenopus are key model organisms for research in cell and developmental biology and biochemistry (12474 publications since 2008). Gene editing has allowed efficient site-directed mutation and knock out production in Xenopus so they are also becoming widely used models to study genetic diseases. The EXRC distributes 2500-3500 resources annually to around 200 laboratories that use Xenopus worldwide, but concentrated in the UK and mainland Europe. A combination of molecular resources (activity funded by BBSRC) and animal-based resources (funded by WT) are sent out to users. The latter includes wild-type and inbred strains of Xenopus, properly characterised transgenic and mutant lines, oocytes, embryos, tadpoles and egg extracts. The centre also makes transgenic and mutant lines, acts as a research hotel and provides the HO amphibian training module. In the next grant period we propose to continue these activities and to supply egg extracts from transgenic lines that have sub cellular components labelled, to use CRISPR/Cas to label cell types that have been unsuccessfully targeted using traditional transgenesis methods, to make more signalling readout lines and, exceptionally, to provide a full cost service for researchers unable to come to use the research hotel but who need to use Xenopus for specific experiments.

Lay abstract: The oocytes, eggs and embryos of the clawed frog (Xenopus) are used to study biochemistry, cell biology, developmental biology, pollution effects and genetic diseases. They have an extraordinarily strong track record of success as experimental tools in these areas; for example, much of what we understand about controlling cell division was found using them and this underpins many modern treatments for cancer. These studies have been enhanced in recent years by the advent of genetically altered frogs that let scientists see particular cell types develop in the embryo by making them fluoresce or even visualise sub-cellular structures in the same way. These GA lines are difficult and time consuming to make and characterise so it is important that individual labs do not make them in isolation, wasting time and scarce funds; resource centres collect, make, characterise and distribute the lines. This application is to fund the largest of these centres.

Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Academic DNA-Encoded Library Resource
Funder: Wellcome Trust

Abstract: Our goal is to enhance and accelerate the validation and translation of new drug targets identified by the UK academic biomedical research community. In order to achieve this we will establish a DNA-Encoded Library (DEL) screening resource that will provide cost-free and commitment-free access to high-throughput compound screening for academic research groups, by; 1) Designing and preparing DNA-encoded libraries containing 5-10 million diverse and drug-like compounds, representing a unique resource for academic researchers. 2) Utilising these libraries to undertake 40 target selections against novel protein targets for academic users, delivering validated hit compounds to >20 research groups by 2025. 3) Developing a sustainable and expandable resource which will continue to deliver beyond the current funding period. DELs are an established screening approach that are utilised by the majority of large pharmaceutical companies. The technology allows for the rapid identification of ligands for a target protein with a very simple protocol compared to other screening approaches. Active compounds are identified by affinity selection of protein-binding compounds from libraries containing millions of different compounds that are each linked to a unique DNA sequence. The DNA tag allows for rapid and high-throughput deconvolution of the active compounds by next-generation sequencing.

Lay abstract: Scientists are constantly making new discoveries about how specific proteins can contribute to human diseases. Once these connections have been identified it is often necessary to find new ‘tool compounds’ that can be used to test whether drugs that affect these proteins could have beneficial effects for patients. Unfortunately, due to technical challenges and high cost, the technology needed to find such compounds is currently hard to access. DNA-encoded library (DEL) screening utilises the power and precision of molecular biology to find active compounds from mixtures of millions of different structures. This has been shown to be a successful alternative to the traditional methods, but the technology is not available to university researchers. We will establish a centre that will use DEL technology to identify tool compounds for more than 20 new targets, allowing researchers to take next step towards the discovery of new drugs.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Single Cell Expression Atlas
Funder: Wellcome Trust

Abstract: Single Cell Expression Atlas (https://www.ebi.ac.uk/gxa/sc) is an open science resource that offers powerful searches for a gene expression data in different cell types, across tissues, species and conditions. Since its launch in May 2018, the Single Cell Expression Atlas has annotated and reanalysed 132 single cell RNA-Seq (scRNA-Seq) experiments across 12 different species that can be searched and visualised through its web interfaces. The SCEA is unique in that it reprocesses raw scRNA-Seq data in a standardised way. This proposal aims to keep up with the rapid technology development, expand the resource with new data modalities, continue expanding the species coverage and cross-species mapping and expand the functionality of the resource. In particular, we will integrate single cell data sets from spatial and in-situ transcriptomics technologies, as well as emerging single cell omics protocols. Additionally, we will expand the types of analyses performed to facilitate study integration, cell type discovery and annotation. Finally, we will develop anatomograms at the organ, tissue and cell type level to enable intuitive interpretation of the experimental results and easily integrate the different types of data on the user interface.

Lay abstract: Single Cell Expression Atlas is an open access database providing the ability to perform powerful searches and analysis of single cell gene expression data. Data is generated by re-analysing raw experimental data to high standards. To meet growing demand, we will develop new analysis pipelines to ensure robust results and extend the level of annotation for genes and cell types in new areas of research. Continued web interface improvement will allow researchers to visualise ever more complex data in an easy way to understand. This provides any biological researcher with the ability to reliably reanalyse data from multiple experiments and further progress their research. Increasing numbers of datasets requires changing from a study specific view to that of whole biology. This will be developed alongside a user interface enabling easy interpretation of gene changes at cell level between health and disease and so enable more rapid progress in research areas.

Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Connecting three worlds: socialism, medicine and global health after WWII
Funder: Wellcome Trust

Abstract: The project pioneers a new history of global health that, for the first time, incorporates the socialist world - a constellation of countries in a fluctuating political, economic and military nexus distinct from the capitalist West. It identifies the particular health cultures produced by socialism (in all its variety) and explores the impact of socialist internationalism in co-producing global health in the 20th century. This project offers a radical new account that will not only transform our knowledge of historical processes, but will further our understanding of ideas, practices and processes that current global health structures have been built on. Global health histories are framed mainly through American, colonial and liberal perspectives. The omission of socialist contexts, however, distorts our understanding of what global health is. Although there was not one socialist template, diverse framings of socialist medicine played major roles in shaping and contesting global practices. A systematic analysis of socialist medicine and international health through global case studies integrates missing expert networks, political agendas, public health models and diplomatic agreements in global health history. This work, in turn, allows us to rethink concepts such as socialism, solidarity, development, socialist medical research and health provision.

Lay abstract: Until recently, the history of global health has been written mainly through the lens of American, colonial and liberal perspectives, without acknowledging the contributions of the socialist world. Though those histories have provided insightful accounts of the forces and processes of health care internationalization, they have also distorted our understanding of how global health came to be produced during the 20th century. Particularly during the Cold War period, different framings of socialist medicine played major roles in shaping and contesting global practices, and our aim is to bring them to the fore. Through case studies located in different regions of the world (Eastern Europe, Africa, Asia and Latin America), we aim to integrate missing expert networks, political agendas, public health models and diplomatic agreements in global health history. This work, in turn, allows us to rethink concepts such as socialism, solidarity, development, socialist medical research and health provision.

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Extension Request for Wellcome Centre for Cell-Matrix Research
Funder: Wellcome Trust

Abstract: Matrix accounts for two-thirds of total protein mass and provides the scaffolds necessary for cell function and tissue health. Consequently, matrix dysregulation is central to ageing and the pathogenesis of major human chronic diseases affecting all organ systems. Discoveries in the Centre have shown that synthesis and degradation of matrix is under circadian clock control, we have identified immunomodulatory pathogen proteins that tether to the matrix during gut infection, and have identified specialised adhesion complexes that mediate cell migration, division and attachment to matrix. We are learning how to regulate matrix synthesis, have unravelled the disease mechanism in a chondrodysplasia, and developed a biologic for the treatment of osteoarthritis and dry eye disease. These, and other Centre discoveries described below were only possible when researchers with complementary approaches worked together in a collaborative environment underpinned by exceptional core facilities. Importantly, we have learned the value of incorporating bioinformatics and mathematics into our research programmes. We are applying for a 2-year extension to our Core Award to implement predictive mathematical modelling, machine learning, and bioinformatics throughout the Centre, maintain our Core Facilities and make ground-breaking discoveries that underpin all of biomedical research and translation combined with a strong public involvement programme.


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