NIHRDataInsights/HRCSData huggingface dataset:
Title: Acellular Approaches for Therapeutic Delivery: UK Regenerative Medicine Platform Hub Application
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Our Hub is concerned with the problem of how a cell or drug therapy for regenerative medicine can arrive at the site of action in an optimal state for rapid and complete tissue formation. Our approach is to design new generations of acellular matrices that create 3D environments that promote tissue formation. We propose that for cell therapies to be efficacious and reliable we must ensure that the cells arrive at the site of action with high viability, minimal physical and biological disruption and with a self-assembling niche that can host, in collaboration with local signals within the patient, spontaneous tissue formation and integration. Overarching scientific principles of these core activities are: 1. The need to mimic hierarchical structures that control cell and tissue behaviour during development and tissue function. 2. Spatial and temporal control of molecular and mechanical stimuli. Tissue morphogenesis and repair use cascades of signalling molecules over periods of hours, days, weeks and months to control cell behaviour. These signals are interpreted by cells in the context of the local mechanical environments and the presence of co-signals (eg integrin mediated cell adhesion). 3.A single cell therapy will encounter numerous changes in environment from manufacture to engraftment. The delivery system should be a chaperone to protect the cell or drug payload against environmental changes. 4. All delivery systems must be able to be translated into clinically and commercially viable products. Therefore, delivery goals should be achieved with the simplest solutions bearing in mind the regulatory process and the risk/benefit of the final product.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: UKRMP Safety Hub
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We will conduct facilitated stakeholder engagement through a series of workshops and reports, informed by experimental progress in this and the partner Hubs, to develop a consensus on how best to assess whether a new regenerative medicine therapy is safe in man. Synthesis of tracking particles (SPIONs, gold nanorods) and development of associated polymer coatings to ensure stability, long-term retention and optimised imaging performance for MRI and photoacoustic imaging (plus multimodal imaging) will build on our recent demonstration of systems exceeding commercial benchmarks. Evaluation of emergent 19F methods will take place and, if warranted, developed further. Reporter genes will be used to indicate cell viability in combination with the nanoprobes. Nanoprobe viability and safety will be assessed with KSPCs, macrophages and HLCs. Biodistribution will be monitored by whole animal imaging in kidney (FA tubular and ADR glomerular) and liver (CCl4 liver fibrosis: macrophage- and ESC-based therapy) disease models. We will assess the biological response of both target and non-target tissues, using organ-selective translational biomarkers of toxicity e.g. mir-122 for liver and Kim-1 and NGAL for kidney, which will link the animal studies and subsequent clinical application of the RMTs. We will use hepatic functional markers such as albumin, and markers of hepatic cell death coupled with metabolic function assays. Kidney tissue damage will be monitored by SPECT/PET and MRI coupled with FDA qualified biomarkers of renal toxicity. Inflammation, systemic toxicity, fibrosis, maldifferentiation and tumourigenesis will be assessed. Regular dialogue with Regulators and commercial partners will ensure all regulatory requirements for the utilisation of novel nanoprobes in early clinical trials are met, with a specific focus on macrophage cell therapy to stimulate liver regeneration and reduce scarring in cirrhosis(aimed to progress to a Phase I trial during the grant).


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: WormBase: an evolving resource for nematode biology
Funder: Biotechnology and Biological Sciences Research Council

Abstract: This application will support two of six UK posts working on WormBase, the established community database for the genome and biology of the Caenorhabditis elegans - a key model organism, established through long term strategic support of the MRC - and other medically relevant nematode species. The genomes of several species of parasitic nematodes are already accessible via WormBase and hundreds more are expected over the coming few years. The funding of this proposal will enable the evolution of the resource to maximise the value of these data. Through this proposal we will (a) curate the genome sequence and core annotation for C.elegans and key parasitic nematodes, actively incorporating new data from the literature, and developing new models for rapid, community-driven curation of newly sequenced genomes; (b) provide computational annotation and comparative genomic analysis for hundreds of nematode genomes; (c) revise the core data management infrastructure, to support the necessary increases in scale that will be required ; and (d) integrate and deliver for public access every two months the entire database, built from data collected and curated at all three WormBase groups. To do this efficiently, we will combine in-house tools with the use of sequence analysis, curation and data management software developed with the joint WTSI/EBI Ensembl project for genome annotation, as well as software and standards developed for the GMOD consortium of model organism databases, of which we are a member. WormBase is freely available for browsing and download from www.wormbase.org, and also contributes the genome sequence and gene sequences to the primary DNA and protein databases, and participates in other core biological information collaborations including the GO consortium. WormBase is co-funded by NIH, who support the two US groups and the remainder of the UK group.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Centre for Ageing and Vitality
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Our plans focus on scientific themes which reflect the overall mission of the Centre to increase our understanding of the biology of the ageing process, and how physical activity/exercise and nutritional interventions influence these mechanisms. Our studies will bring together four different programmes of LLHW research. Our major mechanistic research programmes focus on mitochondrial and inflammatory ageing mechanisms which will combine well with our on-going interventions programmes in physical activity/exercise and nutrition. To ensure the cross-disciplinary nature of the LLHW Centre, five core activities have been identified which are specifically designed to facilitate extensive interaction between the four scientific programmes of investigation. Core activity 1: Interventions in animal models: development, optimisation and use of exercise/physical activity and nutrition interventions in appropriate mouse models Core activity 2: Human and mouse tissue resource: collection, storage and processing of human and animal tissues from the intervention studies for use in mechanistic investigations Core activity 3: Epigenetics and transcriptomics: we hypothesise that many of the consequences of both mitochondrial and inflammatory ageing, and their modulation by specific lifestyle interventions, will be mediated by epigenetic mechanisms and associated changes in patterns of gene expression. Core activity 4: Capacity building for future LLHW research: key staff appointments and capacity building PhD and post-doctoral training programmes which will be strictly cross-disciplinary in design, involving both the intervention studies and mechanistic investigations. Core activity 5: Public and policy engagement: ensuring impact for our research is dependent not only upon high quality publications but also increasingly on engaging with public and policy makers. This will be a core activity to ensure that this is given a high priority within our Centre


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Collaborative Computational Project for Electron cryo-Microscopy (CCP-EM): Supporting the software infrastructure for cryoEM techniques.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The aims of CCP-EM will be achieved through two computational scientists based at the Research Complex at Harwell, directed by 10 investigators active in cryoEM. The PDRAs will maintain the necessary infrastructure in terms of community events, software development environment, and collaboration tools. Together with the named investigators, they will consult the whole community on software requirements. Specifically, they will continue to develop the CCP-EM software framework, and integrate existing programs via close collaboration with scientists/developers in the wider community. The framework has been developed in Python/PyQt which is suitable for integration of disparate programmes. A database backend allows recording of compute jobs, and subsequent review or modified re-run. The CCP-EM PDRAs will also organise conferences and workshops, in order to train new students or scientists entering from another field. These events will include training in specific software, and also more general workshops on issues of common interest. The outputs of the project will include an easy-to-install and easy-to-use software suite, additional tools and resources on the web site, a substantial number of training days delivered, and a range of community events and conferences. Usage of these various resources will be promoted by the investigators and the members of Working Group 1, and monitored via downloads and registrations. The PI and the co-investigators will be responsible for linking CCP-EM activities to other structural biology disciplines, and to the international community. In particular, the PI has a background in the CCP4 project for crystallography, one co-I has responsibility for the Electron Microscopy Data Bank at the EMBL-EBI, and one co-I has led the effort to establish a national EM facility.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: The Collaborative Computational Project for NMR (CCPN): data analysis, integration and partnerships for NMR in the biosciences
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Version-3 of the CcpNmr suite has led to new, user-friendly applications with four different components: AnalysisAssign, AnalysisStructure, AnalysisMetabolomics and AnalysisScreen, which each cover different aspects of biomolecular NMR. The programs use a new, modern intuitive graphical interface with drag-and-drop. We will ensure that current and newly developed software components will continue to be easy to use, fully documented and thoroughly tested, with dedicated modules for specialised tasks and means to interact with external programs and services. This will provide flexible tools to support scientific collaborations and advance important areas such as solid state NMR, metabolomics and small molecule screening. To promote CCPN and increase user uptake, together with our partners we will embed CCPN in a broad range of scientific projects, enhancing its impact in the structural biological community. The greatly enhanced flexibility of the code will promote dedicated program adaptation to the working procedures of individual laboratories. We plan to use the modular capabilities of version-3 and the reorganised library of high-level utility functions to allow for more groups to start writing software for their own specific practices. CCPN will also foster its collaborations with industry. The CCPN software will be extensively demonstrated through workshops and documentation. CCPN will continue its crucial role as intermediary between the UK and international NMR community, by fostering contacts with the national NMR facilities, MRC-Francis Crick Institute, HWB-NMR, and Warwick solid-state NMR facility, other CCPs, the international WeNMR, CASD-NMR and NEF efforts. To strengthen the UK NMR community, we will continue the successful series of UK CCPN conferences and teaching programs for all researchers. We will also continue the comprehensive help and support for CCPN users, participate in international efforts in knowledge sharing and exchange of best practices, and engage in training and teaching through workshops, papers and (video) tutorials. Oversight of the project will be maintained by the CCPN Executive Committee, with representative members from the UK NMR community and CCPN's international Scientific Advisory Board.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: How do Smc5/6 interactions with DNA coordinate replication and recombination?
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Structural Maintenance of Chromosomes (SMC) complexes (condensin, cohesin and Smc5/6) play critical roles in orchestrating chromosome dynamics throughout the cell cycle and are essential for the maintenance of genomic integrity. Smc5/6 regulates homologous recombination and replication restart activities, both key to genome stability. We have shown that the hinge-domain of Smc5/6 binds preferentially to single-strand DNA and that the NSMCE1/3/4 subcomplex binds preferentially to double-strand DNA (dsDNA). We propose that these two DNA-binding activities, separated by ~50nm, work together to control, regulate and ultimately resolve complex DNA structures such as homologous recombination and replication intermediates. To investigate and test our hypothesis, we will co-crystallise the Smc5/6-hinge and NSMCE1/3/4 accessory complex with DNA, thus determining the molecular details underpinning each interaction type. For both complexes, we will also look at any concomitant changes in conformation driven by DNA-binding, using SAXS and other biophysical methods, such as FRET. With the structural information obtained, we will create and test defined mutations (in vitro and vivo) for effects on biological function. We will isolate sufficient Smc5/6 holo-complex to enable single-particle electron microscopy and/or AFM-based approaches, examining the structure and conformational changes, in the presence and absence of bound DNA. We will determine if the holo-complex binds preferentially to biologically-relevant DNA structures, such as Holliday junctions, D-loops and fork-like structures, and whether this can occur in the presence of RPA (replication-protein A), and if DNA-interaction brings the head and hinge regions together. These studies will provide insight into the structure, biochemistry and in vivo function of this important complex and lead to an understanding of how Smc5/6 coordinates replication and recombination and its role in maintaining human health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Public archiving and data integration in the era of multi-modal imaging
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The use of imaging modalities spanning the transition from the molecular to the cellular imaging scales such as electron tomography (ET), 3D scanning electron microscopy (3DSEM), soft X-ray tomography (SXT), and correlative light and electron microscopy (CLEM) in biomedical research is growing rapidly. At present there is no established public archiving for this data except for ET data, which is archived in EMDB. In consultations with the EM and cellular imaging communities it is clear that extending public archiving to include these imaging modalities and improving data integration between different scales of imaging would confer enormous benefits with regards to the potential reuse of the data, enabling for instance the problem-centric visualisation of structural data where information from the cellular and molecular scales are combined. In the context on an on-going MRC funded project (grant MR/L007835; MOL2CELL) we have developed EMPIAR - a pilot archive for raw 2D image data related to EMDB entries, and are in the process of developing a web-based Volume browser that will provide integrated visualisation of EMDB and PDB entries where the link between the molecular and cellular scales is provided by segmentation information. In the proposed project we want build on the momentum and experience from the MOL2CELL project to a) extend EMPIAR to support 3D Scanning Electron Microscopy (3DSEM), Soft X-ray Tomography (SXT) and Correlative Light and Electron Microscopy (CLEM) data, b) develop standards for correlative imaging data and for relating sub-tomogram averages to tomograms, and extend the Volume browser to accommodate CLEM visualisation as well as overlays of sub-tomogram averages on tomograms, and c) develop data-harvesting and submission pipelines to EMDB and EMPIAR to facilitate deposition and to improve the quality and quantity of experimental information collected.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Dietary transitions in African cities: leveraging evidence for interventions and policy to prevent diet-related non-communicable diseases (NCDs)
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Our project investigates the changing food and nutrition environment in the context of rapid urbanisation in Africa. The overall aim is to explore food consumption patterns and practices and the factors associated with them in two African cities (Nairobi and Accra). The project is divided into three interrelated work packages. Workpackage 1 will synthesise evidence on current food consumption patterns and practices and explore their social and physical determinants. It will gather all known secondary data on food consumption patterns and practices for the two countries and undertake a meta-analysis of demographic and social correlates of these. A systematic review will be undertaken to explore the current state of knowledge regarding the factors influencing food consumption patterns and practices in urban Africa. Mixed methods data collection will be undertaken including a 24-hour recall to collect information on food consumption and practices. This will be combined with a Photovoice exercise to examine which social and physical factors influence participants' food consumption. This will be supplemented with spatial data on the features of participants' neighbourhoods that may influence food consumption. Findings will be synthesised into a framework map of the factors that influence food consumption in these two African cities. Workpackage 2 will develop context-appropriate policy. It will examine the current range of policies in each country, and explore how they relate to our framework map. We will produce guidelines for encouraging healthy diets and review what interventions could be implemented using a realist literature review to identify what could works in these contexts, resulting in a policy brief detailing potential interventions. Workpackage 3 will focus on knowledge translation and disseminating findings to key policy makers and the public. It will involve a photography exhibition based on workpackage 1, as well as national stakeholder meetings.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: UK Stem Cell Bank Application for Phase V Funding 2017-2020
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The UK Stem Cell Bank (UKSCB) at NIBSC supports UK regulation on research use of human embryos and makes human embryonic stem cell lines available for international research and clinical use as a public resource. The UKSCB activity to date has created a world-class resource centre from which to obtain high quality stem cell lines, scientific collaboration and advice on the early stages of developing regenerative medicines. The UKSCB has established a reputation and broadened its impact in regenerative medicine, including its support for industry, regulators and policy makers. It now proposes to focus on the preparation and distribution of seed stocks of hESC lines suitable for use in clinical trials under European regulation. This will also require state of the art characterisation, quality control and safety testing of stem cell cultures. The UKSCB will also sustain its support for the regenerative medicine community, including training for a cohort of regulatory scientists to support translational research programmes. It is crucial to its mission that the UKSCB is equipped to sustain its resource of materials and expertise, to assure international acceptability and relevance of its output to rapidly developing science and technology. This will be achieved through a coordination of new NIBSC-MHRA regulatory science work-streams (e.g., vCJD detection, expanded genetic datasets) and infrastructure support for the UKSCB project. This will also be supported by supplementary grant applications that will facilitate closer scientific partnerships within the UK regenerative medicine infrastructure and enhance national coordination and governance. This approach will be vital to ensure that the substantial investment made by MRC and BBSRC in the UKSCB provides ongoing benefit to sustain, promote and develop the UK position in advanced therapies, by equipping the UKSCB to address future regulatory science demands for advanced therapies.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE