NIHRDataInsights/HRCSData huggingface dataset:
Title: Setting an Emancipatory Agenda: Disabled People's Research Network
Funder: Wellcome Trust

Abstract: Social science research has long been criticised for failing to improve the life chances of disabled people. Current research agendas are determined ‘top down’ by policy makers, and researchers risk objectifying disabled participants by conducting research ‘on’ them (as opposed to ‘with’ them). Our radical and exciting proposal challenges the status quo by developing an inclusive agenda and establishing a Disabled People’s Research Network. Our vision is to place academic and non-academic disabled people at the heart of research development, and our entire project will be co-produced by working with disabled people’s organisations. Our activities will identify new salient questions and reinvent social science methodology by exploring how the arts and humanities can enable disabled people to evidence and share their lived experiences. We will develop more inclusive forms of knowledge exchange between universities and disabled people, and we will work with policy makers to maximise disabled people’s research impact. We will empower disabled people as agents of change and our activities will include a range of fellowships for disabled people and a highly innovative research training course led by disabled people. Our network will reinvent how universities work with disabled people, in addition to methodological and epistemological development.

Lay abstract: Our approach to leadership and management is radically emancipatory and inclusive. We will establish a Disabled People’s Research Network in Southwest England. The direction and running of the network will be shared with disabled people. All of our activities will be co-produced with disabled people, and we will provide opportunities for engagement in the network by establishing an advisory panel, regional research hubs, and an innovative research fellowship scheme for disabled non-academics. Our vision is an ambitious programme which aims to create new disability research agendas that are shaped and led by disabled people as researchers. In doing so, this programme will shift disability research away from the elitist culture of academia, to instead focusing on addressing the real world issues that matter to disabled people and organisations. This will involve developing new research models and methodologies for collaborative working between universities, disabled people, and local communities.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Everyday Cyborgs 2.0: Law’s Boundary-work & Alternative Legal Futures
Funder: Wellcome Trust

Abstract: Everyday cyborgs are all around us. They are persons with attached and implanted medical devices; e.g., artificial joint replacements, pacemakers, total artificial hearts, and limb prostheses. Everyday cyborgs are integrated persons - the literal integration of the biological person with the technological. Increasingly, the technologies involved are integrated goods; i.e., devices which not only have a physical existence, but which are also capable of running software and of collecting, analysing, and transmitting data. Because the law takes a bounded approach to person and objects, this conjunction of humans and technology generates unexpected practical, conceptual, and normative problems. This Investigator Award aims to tackle these by challenging law’s boundary-work and radically (re)imagining its approach to the assemblage of integrated persons and integrated goods. It will investigate where and why boundaries occur, examine what the pitfalls and opportunities are when these are transgressed and dissolved, and go beyond the bounded selves conception of persons to develop a novel account of the everyday cyborg in law. This account will be empirically-informed and practically useful, and have solid conceptual and philosophical underpinnings. To these ends, the research will adopt an iterative and flexible cross-disciplinary approach, consisting of complementary conceptual, empirical, and normative analyses.

Lay abstract: Everyday cyborgs are persons with attached and implanted medical devices; e.g., joint replacements, pacemakers, and limb prostheses. Increasingly, these devices are smart devices. They run software and have wifi capabilities. They collect, analyse, and transmit data. However, their integration with persons creates difficulties for the law. Unanswered questions include: (1) should internal medical devices which keep the person alive be viewed as part of the person or mere objects (or something else)?; (2) is damage to neuro-prostheses personal injury or damage to property?; (3) who ought to control/own the software in implanted medical devices?; and (4) how should the law deal with risks around unauthorised third party access and hacking? Building on preliminary research, I will answer such questions. I will use written documents, interviews, and focus groups to better understand the challenges, and test a series of imagined legal futures to assess what is practically possible and suggest solutions.

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Tethered exosomes and their role in MHC-II presentation
Funder: Wellcome Trust

Abstract: Peptide-loaded MHC-II (pMHC-II) is presented at the surface of antigen presenting cells and it has historically been assumed that pMHC-II is localised on the plasma membrane. However, immunofluorescence data reveals pMHC-II localised to patches rather than uniformly distributed. The loading of peptide onto MHC-II occurs within MVBs, specifically on ILVs. In order for pMHC-II to be subsequently incorporated into the plasma membrane, ILVs would be required to ‘back-fuse’ with the limiting membrane of the MVB. This back-fusion step represents an ambiguous fusion event. I have recently shown that exosomes can be physically tethered to the cell surface by tetherin. Tetherin is highly expressed in antigen presenting cells and these cells display clusters of exosomes at their surface. Using biochemistry, immuno-electron microscopy and functional assays I wish to test the hypothesis that surface-tethered exosomes present pMHC-II at the surface of antigen presenting cells. I will establish the molecular machinery which traffics tetherin to ILVs/exosomes, and define the residues on tetherin that are required for this trafficking. Finally, I will explore where and how exosomes fuse to recipient cells, and use a screening approach to identify molecules involved in exosomes – plasma membrane fusion.

Lay abstract: Exosomes are vesicles that are released from cells upon fusion of internal compartments (endosomes) with the surface of cells. It has been assumed that upon their release from cells, exosomes deliver their contents to adjacent cells, providing communication between cells. I have recently shown that exosomes can be retained in clusters on the surface of cells following their discharge, opening up potential new roles for exosomes. The retention of exosomes is dependent on a protein called tetherin, which plays a similar role in the tethering of newly budded viruses. The function of tethering exosomes is unknown. Cells of the immune system generate high levels of tetherin and present clusters of exosomes on their surface, but why? I will test the hypothesis that tethered exosomes contribute to a functional immune system. Further, I will define where and how exosomes fuse when they come into contact with another cell.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of nuclear envelope function and links with disease
Funder: Wellcome Trust

Abstract: The nuclear envelope (NE) lies at the interface between the nucleus and the cytoskeleton. It forms a complex structure controlling cell compartmentalization and regulates many processes including nucleo-cytoplasmic transport of proteins and RNA, chromatin organization, DNA replication and DNA repair. Hence, defects in NE integrity and nuclear architecture cause drastic changes in cell homeostasis and are associated with a broad range of diseases including cancer, premature ageing syndromes, neurodegenerative diseases or muscular dystrophies, but also with physiological ageing. One of the main challenges is to understand how NE defects lead to so many types of diseases. Previous theories include changes in gene expression and mechanical weakness. My previous work has shown that subcellular processes including microtubule or chromatin organization can modulate NE function, and has identified the acetyltransferase NAT10 as a key regulatory node for control of nuclear architecture. My goal is to now investigate how NAT10 and other factors regulate the NE. I will thereby gain new understanding of how of nuclear architecture is orchestrated and how this is disrupted in age-related diseases including HGPS. This research will not only contribute to our fundamental understanding of nuclear architecture but will also potentially identify new therapeutic strategies for NE-associated syndromes.

Lay abstract: Human cells are highly organised and regulated, which is essential for the healthy function of tissues and organs. Recently, it has become evident that one crucial part of the cell is a structure called the nuclear envelope (NE), surrounding the cell nucleus – home to our DNA. The NE is crucial for maintaining nuclear architecture and cell function. Dysfunction of the NE leads to various human diseases, including cancer, muscular diseases, neurodegenerative syndromes and premature ageing syndromes called progeria. The fact that NE defects are associated with various human diseases and with normal ageing has triggered a strong interest in trying to correct the abnormal nuclei and associated defects in NE-associated syndromes, to improve cell “fitness” and patient survival. Unfortunately, there is no effective treatment for these diseases, and the available therapies mainly act by improving the symptoms of these patients. In this proposal, I describe how I plan to characterize new mechanisms that regulate NE function. This work will improve our fundamental knowledge of NE function and will suggest new ways of treating these diseases. Moreover, this work could also open up new perspectives into improving normal age-related pathologies, which would have a great impact on public health.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The quality control of mislocalised membrane and secretory proteins
Funder: Wellcome Trust

Abstract: A network of integrated pathways coordinates protein synthesis and degradation enabling our cells to offset inherent defects, including misfolding and aggregation, and maintain protein homeostasis. The extremely hydrophobic transmembrane domains and targeting signals of membrane and secretory proteins pose a particular challenge, since inefficient subcellular delivery and defective membrane translocation result in the cytosolic mislocalization of these notoriously aggregation-prone precursors. We have discovered that these mislocalized proteins (MLPs) are rapidly removed via a specialised quality control pathway that employs novel adaptors and effectors to regulate their selective proteasomal degradation. What we do not understand are the molecular details of MLP quality control, how it is coordinated with membrane protein delivery and how it is integrated into global protein homeostasis. My primary objective is to define the molecular and cellular basis of MLP quality control by addressing four key questions: 1. How do exposed hydrophobic motifs elicit protein quality control in the cytosol? 2. Client sorting: how does the MLP chaperone network support both the delivery and degradation of substrates? 3. Does the client base for this specialised quality control pathway extend beyond hydrophobic MLPs? 4. How are MLP inclusion bodies formed and what is their fate?

Lay abstract: Proteins are essential to life, providing important building blocks and performing complex roles that maintain health and combat disease. Making proteins is complicated, so we have systems to recognise and remove any misfolded proteins that arise when things go wrong. The ability to control the quality of our proteins is very important, since faulty proteins often clump together into potentially dangerous aggregates that are linked to diseases like Alzheimer's and Huntington’s. Rogue membrane and secretory proteins that reach the wrong destination in our cells, collectively termed MLPs, also have a strong tendency to aggregate. However, a specialised quality control process recognises and removes these MLPs thereby avoiding potential problems. We have identified important cellular factors that deal with MLPs by controlling their aggregation and fast-tracking their destruction. It is now vital to understand exactly how these different components work together to deal with MLPs so effectively. By discovering how MLP quality control works, and learning how cells cope when it does not, we will find out why cells can deal with certain kinds of misfolded proteins so effectively and discover how important efficient MLP quality control is for keeping our cells healthy.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Exploring the roles of motile adipocytes in wound repair and cancer
Funder: Wellcome Trust

Abstract: Adipocytes regulate wound healing and cancer through ill-defined molecular mechanisms. My recent work showed that Drosophila adipocytes, fat body cells (FBCs), are motile and migrate to wounds to play local roles in wound healing. Other studies have shown that Drosophila macrophages, hemocytes, are recruited not just to wounds, but also to tumors. Moreover, hemocytes instruct FBCs to counter tumor growth through largely unknown mechanisms. I propose 3 projects using live imaging in the genetically tractable Drosophila pupa to investigate the functions of motile adipocytes in wound healing and cancer: 1. Building on my recent finding that FBCs are needed systemically for reepithelialisation, I will explore this systemic role of FBCs in regulating wound closure and unravel the underlying molecular mechanisms. 2. I will use FBCs as a model of adhesion-independent cell migration and dissect the mode of migration of FBCs by quantifying actin flow and studying actin regulators. 3. I will study the role of FBCs and hemocytes in regulating cancer growth in a pupal tumor model. I will test whether FBCs and hemocytes migrate to and interact with tumors by live imaging. Using genetic tools, I will deduce the mechanisms by which FBCs and hemocytes counter tumor growth.

Lay abstract: Fat cells, also called adipocytes, were once believed to merely serve to store our energy and keep us warm. It is now clear that they also play important functions in wound healing and cancer. Our recent study in fruit flies showed that adipocytes, commonly presumed to be immobile, are actually motile cells that migrate towards wounds to enable wound repair and fight wound infection. Our goals now are to investigate what roles motile adipocytes have in promoting wound healing and in blocking cancer growth. Using the pupa of the fruit fly we will follow the behaviour of adipocytes in response to wounds or tumors in real time using microscopy and combine this with genetic experiments. Our findings will provide new insights into the mechanisms through which adipocytes regulate wound healing and cancer and may help identify possible new therapies for improving wound healing and inhibiting cancer growth in human patients.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Foundations for routine 3D X-ray histology
Funder: Wellcome Trust

Abstract: Whilst 3D medical imaging is commonplace, microscopic tissue structure analysis (i.e. histology) remains overwhelmingly wedded to ~200-year-old practices of microscopic 2D examination of tissue sections. Building on our first demonstrated assessment of 3D microstructural detail in standard wax-embedded soft tissue (Scott et al., 2015, http://dx.doi.org/10.1371/journal.pone.0126230) we will develop the foundations for routine 3D X-ray histology by: Providing: 1. Robust, non-destructive, high-throughput 3D microscopic imaging of routinely processed soft tissue samples at 5-10 µm resolution. 2. Access to orders of magnitude more tissue structure data per sample (cf. optical sections). 3. Tissue-level volumetric structure and connectivity insights (previously unavailable). 4. Correlative 3D data supplementing other routine or specialist imaging (e.g. immunostaining, laser microdissection). 5. Routes to novel medical and scientific discovery (Jones et al., 2016, http://dx.doi.org/10.1172/jci.insight.86375; Koo et al., 2018, in revision). Establishing: 6. Hardware approaches to increased sample throughput. 7. Standardised, automated workflows for image acquisition, calibration, CT reconstruction, data handling. 8. Long-term roadmap for emerging X-ray technology improvements targeted for biomedical applications. Raising awareness/driving uptake through: 9. Pilot studies (n~10 samples/study)/new applications validated by 2D histology and integrated with correlative imaging modalities. 10. Biomedical case studies (n~100) at high statistical power. 11. Data resources (n~100) for artificial intelligence and deep learning approaches in digital 3D histopathology.

Lay abstract: We have demonstrated that X-ray imaging by micro-computed tomography (muCT) allows non-invasive three-dimensional (3D) imaging of the microstructure of standard tissue biopsies. This yields details comparable to two-dimensional (2D) optical microscope sections but for the whole tissue volume, which can for example overturn misconceptions of disease development based on 2D assessment. Via improved technology, including new X-ray equipment and standardised & automated workflows, sample throughput will be increased and scan times reduced, providing the foundations for day-to-day 3D X-ray histology. This will enhance and facilitate biomedical research. Applicable to vast existing sample archives, and a wide range of soft tissue types, this will open new areas of research, such as large-scale 3D histological phenotyping ("histomics"). This will furthermore translate directly into next-generation clinical image-based diagnostics and patient stratification using artificial intelligence and deep learning. Time-critical intraoperative 3D examination of tissue biopsies will also become possible via the technologies developed here.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: How is embryonic development timed and scaled?
Funder: Wellcome Trust

Abstract: A mysterious question is how cells know for how long they should divide to allow structures such as our limbs to grow to their correct sizes. We work on the developing chick wing bud and we are going to test if two molecules – one that tells the cells to divide and one that tells them to stop dividing - form the mechanism of a growth/size clock. In this hourglass timer model, the level of the molecule that tells cells to stop dividing increases until it passes a threshold that stops cell division and growth. We are also going to test if these growth clocks can be reset in the embryo to an earlier time. If we can use this information to reset limb clocks later in adults, and thus reset development, we might be able to devise clinical strategies to aid limb regeneration. Another enigmatic question is why species have differently sized limbs. We will ask if limb growth clocks run at species-specific rates in a range of birds of different sizes, including quails, chickens and ducks. Understanding how these clocks function can give insights into human disorders in which the timing of embryonic growth is disrupted.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Discovering principles of senescent pathophysiology using a simple animal model
Funder: Wellcome Trust

Abstract: Investigations of genes that affect lifespan have yielded many insights into the regulation of ageing, but have fallen short of identifying the mechanisms of ageing themselves. We have developed a new approach to investigating ageing which uses senescent pathology instead of lifespan as a metric for ageing in Caenorhabditis elegans. This pathology-centred approach examines (i) the causes of individual pathologies, and (ii) the diseases that limit lifespan. Our findings support a new ageing paradigm: the senescent pathologies studied result not from random damage, but from pathogenic run-on of wild-type function (or hyper-function). Such run-on is promoted by pathways that control ageing, e.g. insulin/IGF-1 signaling (IIS). The proposed work will pursue new leads generated by the pathology-centred approach. We shall ask: first, how does yolk production cause late-life disease, and how does IIS promote this? Second, how do different pathways controlling lifespan act by altering different causes of mortality? Third, is extended lifespan in C. elegans attributable to reproductive strategies specific to this species? This work will identify the steps in the causal chain between genes and lifespan, with the aim of establishing general principles of senescent pathophysiology that can guide research on the origins of diseases of human ageing.

Lay abstract: Many genes have been identifed in the simple animal Caenorhabditis elegans that influence lifespan. However, the chain of events between gene function and lifespan, including the core processes of ageing itself, remain largely unidentified. My goal is to identify them through the study of nematode diseases of ageing. The work will build on my recent demonstration that a new paradigm can explain origins of C. elegans diseases of ageing: unnecessary continuation of growth-related processes in later life. I shall investigate how pathways that affect lifespan act to control such late-life run on, how different treatments that extend lifespan act by altering different life-limiting diseases, and the extent to which mechanisms involved affect other species. Ageing is now the main cause of disease worldwide. Understanding its primary causes in C. elegans should reveal basic principles about causes of late-life disease, and inform future medical treatments to improve late life health.

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