NIHRDataInsights/HRCSData huggingface dataset:
Title: Hyaluronan (HA) assembly and its Role in Bone Morphogenic Protein-7 Driven Antagonism of Renal Fibrosis
Funder: Medical Research Council

Abstract: Hyaluronan (HA) is a matrix polysaccharide involved in regulation of cellular processes, and demonstrates increased expression in renal disease. TGF-beta-1 promotes epithelial mesenchymal transition and fibroblast to myofibroblast differentiation. These processes drive renal interstitial fibrosis, which predicts outcome in all renal diseases, and our previous studies have shown that both these processes are mediated by HA. BMP7 is a cytokine demonstrating reduced expression in renal disease. Evidence suggests it can both prevent and reverse TGF-beta-1-driven fibrosis. We have shown that BMP7 modifies cellular HA matrix and there is evidence that HA modulates BMP7 responses. The aim of this proposal is to investigate if the prevention and/or reversal of TGF-beta-1 responses by BMP7 are mediated by the effects of BMP7 on HA matrix. The work will initially utilise fibroblast and renal epithelial cells models and encompass a variety of cell biology techniques to characterise BMP7-driven alterations in HA at a pericellular, cell-surface and cytoplasmic level and relate these changes to TGF-beta-1 driven regulation of cell phenotype. Furthermore, the in vivo applicability and relevance of our in vitro observations will then be investigated by identifying BMP7 driven alteration in HA and HA-related proteins in the kidney in an animal model of renal disease. This work will inform the next steps in terms of identifying suitable HA related targets for the development of knockout animal models, and aid in the development of new therapeutic strategies in progressive renal disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Specification, maintenance and elimination of stem cell progenitors for the mammalian anteroposterior axis
Funder: Medical Research Council

Abstract: The origin and maintenance of tissue stem cells in the embryo is not well understood. We have identified and characterised an in vivo stem cell population with novel characteristics, neuromesodermal (NM) progenitors, which produce the anteroposterior (AP) axis. Disruption of AP axis elongation occurs in a cluster of human syndromes (caudal regression syndrome, Currarino syndrome and sacrococcygeal teratoma). Our recent work has given new insight into the specification, maintenance and elimination of NM progenitors. In this programme, we plan to discover (i) what factors govern the specification of of NM progenitors from the pluripotent epiblast; (ii) the molecules that control NM progenitor maintenance and subsequent differentiation as neurectoderm or mesoderm; and (iii) the hierarchy of events that lead to elimination of NM progenitors at the end of axis elongation. The experiments will make use of existing and new genetic modifications in ES and epiblast stem cells, physical micromanipulation of embryos and embryonic explants, imaging and cell sorting. This programme can therefore contribute significant understanding of an in vivo stem cell, shed light on the origin of common birth defects, and provide a novel, non-neoplastic source of spinal cord and mesoderm cell types that are currently refractory to in vitro isolation, such as skeletal muscle and intervertebral disc progenitors for therapeutic applications.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A Systems Approach to Understanding Methylation Programming in Oocytes and its Consequences in Development
Funder: Medical Research Council

Abstract: We aim to provide an overarching account of DNA methylation in oocytes, its consequences and vulnerabilities. The work will be conducted mostly in the mouse as the model of choice for understanding epigenetic processes in gametes and preimplantation embryos. The connections we shall explore between transcription and methylation are based on known properties of Dnmt3a and Dnmt3L - which constitute the de novo methylation complex active in oocytes and which is believed to sense histone modifications - and histone modifying factors with evidence for transcription-coupled activity. Of particular interest to us is methylation of H3K4 and H3K36, which can be modified in response to transcription. We shall use conditional knock-outs for factors of the Kdm1 and Kdm5 families, which regulate H3K4 methylation, and we shall mutate Dnmt3a so that it is no longer binds the transcription-coupled mark H3K36me3. We shall map transcription units and promoter activity and how they change during oocyte growth, and correlate this with timing of DNA methylation in specific genes. We shall ablate specific transcription factors expressed in oocytes, and investigate whether this leads to predicted changes in gene body and intragenic CpG island methylation. This will be done with conditional alleles for transcription factors with known roles in oogenesis, but we shall also identify additional transcription factors with effects during the de novo methylation phase of oocyte growth by informatics analysis of expression and transcription start site datasets. We shall use our highly sensitive DNA methylation profiling (RRBS) as an endpoint in many of these mechanistic studies. We shall use RRBS (and other techniques we might develop) to profile changes in methylation in oocytes and embryos in response to manipulations in maternal diet and superovulation. We shall also profile DNA methylation in human preimplantation embryos to identify conserved sites and properties of DNA methylation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Research partnership to assess the burden and aetiology of non-communicable diseases (NCDs) in sub-Saharan Africa (SSA)
Funder: Medical Research Council

Abstract: The overall aim is to develop a sustainable partnership that will facilitate multi-centre research to assess the burden and aetiology of NCDs in SSA to improve the evidence base underpinning potential responses to NCDs, provide a platform for interventional research in NCDs, and to ensure that African populations benefit from the ongoing advances in genomics. Specific objectives are to 1) establish a consortium of investigators and research institutes capable of conducting multi-centre research into NCDs in SSA; 2) devise and develop guidelines for research governance and scientific strategy for the NCD partnership; 3) devise and maintain a web-portal for sharing data, research resources (data collection tools and software, e-questionnaires, protocols, SOPs, analytical plans), and research training tools with the wider scientific community; 4) facilitate capacity strengthening, provide research training, and identify mechanisms to develop infrastructure for NCD population based research (observational studies, including genomic analyses, and intervention trials) in SSA; 5) enhance ongoing studies across the partnership by facilitating pooled collaborative analyses across multiple regions of SSA; and 6) develop partnership-wide research funding proposals.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Establishing The Edinburgh Super-Resolution Imaging Consortium (ESRIC)
Funder: Medical Research Council

Abstract: We are requesting funding to establish the 'Edinburgh super-resolution consortium' (ESRIC), bringing together a large cohort of high-profile cell biologists with engineers, mathematicians, physicists and chemists. We request funds for 3 imaging platforms: a gSTED and white-light-laser (WLL) upgrade to an already UK-unique Leica SMD (single molecule detection) FLIM and FCS system, and Nikon SIM and STORM systems: all platforms will be openly accessible to optical physicists for add-on modification and data analysis development. The WLL upgrade will permit the use of any fluorohore in the visible range in STED, FLIM and FCS experiments. With these additions, ESRIC will contain every current super-resolution imaging and spectroscopic approach in a managed facility able to be accessed by a wide audience of biologists with internationally recognised research programmes, providing platforms to quantify cell biology over a range of scales from single molecules to the intra-vital, matched by expert signal processing, mathematical and physics input to create the 'next generation' of imaging approaches and analyses. No single imaging technique can address the various questions asked by modern biology and additionally, comparing data across imaging approaches is important. For example, PALM is (currently) limited to TIRFM-illuminated-sections at the base of cells, whilst gSTED can be used anywhere in 3-D at high frame rates. Super-resolution imaging cannot quantify protein interactions but combined with FLIM and FCS here, users will be able to do this. PALM and STORM require software reconstructions; comparing such data with gSTED and SIM can confirm that molecule localisation maps correlate with true sub-diffraction-sized structures. Also importantly, we have assembled an inter-disciplinary team who will work closely with the biologists in ESRIC to refine and deliver the next generation of imaging technologies, instrumentation and analytical approaches.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Multiparametric advanced fluorescence imaging strategies for in situ analysis of live cell signalling
Funder: Medical Research Council

Abstract: The power of optical imaging technology to drive major discoveries in cell biology and medicine has increased dramatically over the last decade. This proposal focuses on two areas of fluorescence microscopy where the potential for such applications is clear but has not yet been fully realised. The first relates to functional imaging modalities that can map specific protein-protein interactions in cells, in particular using Forster resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM). The second relates to super-resolution microscopy (SRM) methods that break the conventional resolution limit imposed by the wavelength of light. In recent years, many different SRM technologies have been developed that typically promise a spatial resolution of 50 nm, an order-of-magnitude improvement over conventional methods. However the commercially available FLIM and SRM instruments are limited by technical constraints of sub-optimal detector sensitivity, speed, data analysis and interpretation. We will develop new FLIM and SRM configurations and detectors to overcome these limitations, and allow protein location, orientation, environment, interactions and dynamics to be analysed in living cells and organisms. These instruments will all be built within a new Microscopy Development Centre (MDC) on the Guy's Hospital Campus of King's that is adjacent to the new Nikon Imaging Centre. These two Centres will share technical support, training, data storage and image analysis facilities/expertise. The MDC physicists will work closely with biomedical scientists in the co-I's teams to refine the new instruments and apply them to a series of exemplar biological questions in the fields of immunology, stem cell biology, cancer, cardiovascular and muscle biology. Once developed, the new FLIM and SRM technologies will be disseminated within the biomedical research community, initially within King's and subsequently to other UK Universities, institutes and companies.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: SHeffield IMAging (SHIMA)
Funder: Medical Research Council

Abstract: Super-resolution (SR) microscopy is beginning to allow exciting new discoveries to be made across biomedical and biological disciplines. Rapid and widespread application of the new technology has been hampered by the lack of robust, affordable commercial systems and the dearth of compatible probes. We aim to establish a world-class centre in SR imaging based on our existing strengths in technology development and its biomedical application, the proposed project and a significant investment by the University of Sheffield. We will utilise commercial Structured Illumination Microscopy (SIM) and Stochastic Optical Reconstruction Microscopy (STORM) systems in a range of applications but, crucially, also embed the commercial instrumentation within a culture of technology development via a new centre for biophysical imaging. This will ensure that emerging technologies are quickly translated into wide usage by the biomedical community, further enhanced by our close association with industry, ensuring translation of our developments. At the outset we have identified probe development and increasing the image acquisition speed of STORM as key goals for our programme. The University of Sheffield will make a direct investment in the project by funding a senior experimental officer, refit of a new microscopy development facility, PhD studentships and a contribution towards the large equipment costs. The 5-year duration of the funded programme will ensure the optimal development and application of SR microscopy across the University, with greatest impact. Our ambitious project will be significantly enhanced as imaging is a flagship initiative for the University of Sheffield, creating a vibrant interface of technology to fully exploit the potential of the technologies within the context of their application to generate new levels of biomedical understanding.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE
Title: MRC Centre for Regenerative Medicine
Funder: Medical Research Council

Abstract: The proposed research of the Centre over the next 5 years is comprised of three parts. First, our research programmes addressing key gaps in fundamental knowledge (tissue stem cells, plutipotent stem cells, niche composition and regulation, activation of tissue stem cells, stem cell differentiation and reprogramming), translation (drug-based therapies, cell-based therapies, disease modelling) and clinical application (cell therapies for liver disease, regenerative neurology) that represent the continuation of our activities catalysed by the initial Centre award - these programmes are now funded by programme and project grants. Second, the new collaborations and strategic initiatives we propose to achieve our ambition of being world-leading in the field of stem cell and tissues - it is to create these new collaborations and initiatives for which we seek MRC support in this renewal application. Third, the new translational and clinical platforms for which we propose to leverage our MRC Centre status, and the explicit recognition by the MRC of our ambition, to generate additional funding from other sources. These are an academic cell therapy unit and an endogenous repair platform to contribute to the UK Regenerative medicine platform and a new clinical programme in cardiovascular regeneration in partnership with the BHF. From this research we will deliver a detailed understanding of the array of external and internal signals that instruct stem cell behaviour and tissue formation, show how disease modifies these signals and identify the steps in the regenerative process at which repair then fails. Using this knowledge, we will generate better animal- and iPS-based models of relevant diseases. We will use these to devise strategies to promote regeneration that we will test in first-in-man clinical trials, so using our facilities and our vision to deliver the crucial next impacts in stem cell biology and regenerative medicine.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Role of Thrombospondins in interstitial Extracellular Matrix 3-Dimensional Organisation: Mechanisms and Functions
Funder: Medical Research Council

Abstract: The extracellular matrix (ECM) is an essential component of the tissue environment of cells. Molecular composition, 3-dimensional (3D) organisation and mechanical properties of ECM all provide important cues that control cell phenotype and the assembly of body organs. Standard 2D cell culture does not replicate this environment and the processes by which 3D tissue ECM assembly is maintained through life are poorly understood. This is a major challenge in the ECM field: for example, for in vitro handling of stem cell populations, to maintain cells close to their in vivo differentiation state, or to understand effects of ageing or chronic diseases that are increasing health problems in the UK and worldwide. Progress with advanced cell culture can help reduce and replace animal use in medical research. This application aims to understand molecular systems that support proper assembly of 3D interstitial ECM. We approach this question with a focus on thrombospondins (TSPs), because of recent appreciation that these are very highly-conserved accessory ECM proteins and because of evidence for roles as modulators of collagen fibril organisation in mammals. Aim 1. Recent data have led us to a novel, unexpected model of a conserved mechanism for how TSPs are deposited into ECM. The mechanistic goal is to understand this process at molecular and cellular levels. Aim 2. To Identify the specific roles of ECM-bound TSPs in interstitial ECM organisation in vivo. We will examine the roles of ECM-accumulation of TSP1 in the interstitial ECM of mouse dermis, under homeostatic conditions and in the tight skin mouse that has fibrotic excess of dermal ECM. Aim 3. To elucidate how mechanisms of ECM-accumulation of TSP1 impact on organisation and functions of fibroblast-derived 3D ECM and fibroblast phenotype. Mechanisms identified in Aim 1 will be related to fibroblasts and their native ECM, exploiting fibroblasts from the new genetically-modified mice developed in Aim 2.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Scottish Collaboration for Public Health Research and Policy
Funder: Medical Research Council

Abstract: SCPHRP was established in 2008 to utilise modern principles of successful knowledge transfer and exchange, with the aim of improving Scottish health and reduce its steep health inequalities. Our mandate was to create stronger links between Scottish public health researchers, and the potential users of that research, in policy, programme and practices settings throughout the country. We have done this by creating four Working Groups, spanning these communities. Those processes have led to more context-sensitive, policy relevant research projects being designed and funded, initially through 20+ SCPHRP seed grants in 2009-12. More recently, spin-off multi-disciplinary teams have won four major public health intervention and E-Health grants, funded by UK-level research agencies (NIHR and MRC). In its second quinquennium, SCPHRP will refine its vision, to develop Scotland as a leader, in Europe and the world, in public-health intervention research for equitable health improvement. We will pursue that mission through continuing to catalyse strong researcher/research-user connections that ensure timely, high-quality, relevant research, and its actual use in policy, programme and practice. This will contribute to better value-for-money in public services, through more comprehensive and robust evaluation of how successfully current public sector initiatives improve health status, and do so equitably. SCPHRP's new programmes of research and knowledge transfer/exchange will address the following overarching scientific themes, to advance the science of equitable health improvement, especially through secure, anonymised cross-sectoral record-linkage: 1. Methodological development in monitoring health inequalities, using more promptly-sensitive outcome measures; 2. Assessment of patterns and time-trends in health inequalities in Scotland to guide intervention development; 3. Robust evaluation of public health interventions, including 'natural experiments'.


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: DECIPHer: Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement
Funder: Medical Research Council

Abstract: Multiple risk behaviours: Complex analyses of large scale longitudinal data sets including latent class analysis, with further analyses attempting to identify longitudinal relationships between multiple correlated determinants at multiple time points on the one hand, and multiple risk behaviours and their development over time on the other. Systematic reviews of the literature, including new methods which systematically identify and synthesise relevant social theory. Health promoting settings: Transdisciplinary action research partnerships including: repeated measures data collection to inform needs assessment and strategy development, longitudinal evaluation and a data rich environment for system dynamics methods to be developed and applied to the modelling and adaptation of interventions; engagement of stakeholders to maximise ownership and maintenance of interventions; multilevel programmes, following a standard functional design based on evidence and theory, but optimised for local circumstance and need. Complex intervention research: Mixed methods randomised trials of complex interventions. Further development will be in the analysis and dissemination of how to design and deliver such studies in the real world, contributing to methodological literature in policy trials and implementation science; developing the concept of realist trials; improving reporting and synthesis of complex trials; modelling of complex systems and relationships - agent-based modelling, social network analysis, and of long term cost-effectiveness. Data linkage and natural experiments: Exploitation of data resources created through data linkage to facilitate natural experiments of population health interventions. This will include development and refinement of novel research designs, informed by engineering based systems science methods, to use repeated measures data to monitor, evaluate and improve interventions. We will further develop the Welsh Electronic Cohort for Children.


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