NIHRDataInsights/HRCSData huggingface dataset:
Title: Cell signalling by protein tyrosine phosphatases
Funder: Wellcome Trust

Abstract: The protein tyrosine phosphatases (PTPs) are important regulators of cell behaviour and function with kinases to control phosphotyrosine levels. Phosphatases are often seen as an off-switch in signalling, however several PTPs promote downstream signalling. The PTPs are known to be regulated by reactive oxygen species (ROS), which function as second messengers in numerous processes such as growth factor signalling and wound healing by targeting protein cysteine residues. After discovering direct substrates for a receptor-type PTP, we now find that its interactions with these proteins are surprisingly redox-sensitive. I hypothesise that PTPs function as redox-switchable scaffolds, promoting protein complex formation in response to ROS in cells. I will combine biochemistry, cell biology and optogenetic approaches with quantitative mass spectrometry to test this hypothesis. To this end, I will define the molecular details of a PTP redox complex, the signalling pathways that promote cellular PTP oxidation and the sufficiency of PTP oxidation to trigger cell signalling events. The results will shed light on a new signalling mechanism and could yield alternative approaches to therapeutically target the PTPs in numerous disease settings.

Lay abstract: Cell surface receptor proteins receive and send signals to the cell interior. They achieve this by utilising chemicals such as hydrogen peroxide (H2O2) to transmit signals between proteins. The protein tyrosine phosphatase (PTPs) are targets of H2O2. H2O2 is currently thought to inactivate PTPs in order to block their antagonism of kinase enzymes. However, I have shown that H2O2 causes specific shape changes in PTPs, promoting interactions with other proteins. I hypothesise that PTPs are critical nodes in transmitting signals using H2O2. To test this, we will reveal the molecular details of PTP-protein interactions, identify how H2O2 is generated in cells and use novel tools to manipulate PTPs and visualise the effects on cell signalling by microscopy. This will not only uncover how PTPs work in healthy cells and disease, but could also help in designing new strategies to target them therapeutically.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Warwick-Wellcome Trust translational Partnership
Funder: Wellcome Trust

Abstract: The University of Warwick will use the partnership to invest in fellowships and projects that focus on impact in the science of early life, human tissue models of disease, and disease control and prevention. The partnership will also enable the provision of supporting expertise in impact delivery, and strengthen links with partner institutions in both industry and our local hospital network.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE
Title: An Integrated Understanding of the NuA4 Coactivator Complex
Funder: Wellcome Trust

Abstract: Coactivators SAGA and NuA4 stimulate transcription by post-translational modifications of chromatin, but also have important roles in DNA repair and mRNA export. Both contain Tra1, a highly conserved 3744-residue protein that belongs to the Phosphoinositide 3-Kinase-related kinase (PIKK) family. Tra1 enables targeting of SAGA/NuA4 to specific genes, by directly interacting with DNA-bound activator proteins, but the molecular details are unknown. Understanding how Tra1 functions within these complexes is critical for elucidating how they cooperate and function in multiple processes. By combining structural, functional and systems biology techniques, we will focus on the Tra1 protein and the NuA4 complex to produce an integrated understanding of their functions. We have two key goals: (1) determining the molecular mechanisms behind activator targeting of Tra1 and their importance for SAGA and NuA4 recruitment during gene activation and (2) solving a complete and high-resolution structure of the NuA4 coactivator complex that will provide an integrated understanding of its functions in transcription and DNA repair. We also have preliminary data in new projects that will expand our research programme beyond the fellowship, by exploring the mechanisms of Tra1 in DNA repair, the relationships between different PIKKs, and the structure and function of histone methyltransferase complexes.

Lay abstract: Complex programs of transcription define cellular identify and function, and are established by combinations of activators and coactivators. Coactivators catalyse chromatin modifications and recruit the transcriptional machinery to stimulate gene expression, but they lack DNA specificity and must interact with sequence-specific activators for targeting to specific genes. The highly conserved chromatin modifying coactivators SAGA and NuA4 associate with activators via the Tra1 subunit that is common to both complexes. In addition to transcription regulation, they also have additional roles in DNA repair and RNA transport. However, their size and complexity have limited our understanding of their mechanisms and functions. We will investigate the molecular mechanisms of Tra1 by examining its interactions with activators and determining their effects on recruitment of SAGA/NuA4 and subsequent mRNA production. This will be integrated with our cryo-EM studies of the complete NuA4 complex, providing an integrated understanding of this multifunctional and important macromolecular machine.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Next generation atomic force microscopy for solving problems in biomedicine
Funder: Wellcome Trust

Abstract: AFM has unique capabilities for understanding life, and is able to image living systems in their native state under physiological conditions with molecular resolution. However, technologically, it is where EM was in the 1990s – far from delivering its theoretical potential when imaging biology. By understanding the physical principles of the technique and systematically optimising the instrumentation, the potential of EM has been unleashed in recent years. We aim to drive a similar “resolution revolution” in AFM, developing an instrument that can: 1. Image functioning biological molecules in intact systems, including living cells, without perturbing their function or structure. 2. Obtain these images with sufficient resolution to identify biomolecules by their topography. 3. Accurately measure the organisation of biological molecules in complex, native samples. We will do this by targeting fundamental weaknesses in AFM technology: 4. Reducing the thermal noise of the cantilever by producing smaller and softer cantilevers, and a microscope that can use them, reducing the imaging force 10-100x compared to the current state-of-the-art. 5. Reducing positioning noise and drift by developing a hierarchical, interferometric closed-loop scanner that reduces noise by >10x and drift by 100-1000x compared to the current state-of-the-art, providing traceably accurate measurements of size and position.

Lay abstract: Advances in microscopy can change how we see the natural world and repeatedly lead to breakthroughs in biomedicine. Atomic force microscopy provides unique capabilities, being able to image living samples with molecular resolution, in liquid, at room temperature with minimal preparation. However, for biomedical applications it has failed to live up to its potential, arguably because instruments truly optimised for biology have not been developed. We will push each aspect of the microscope towards its theoretical limit to develop a new instrument that can image biomolecules with resolution comparable to structural biology approaches, but in context, under native conditions. These same advances will also allow us to measure the tiny forces that drive living processes. We will use the instrument to help understand pressing biomedical questions including: how bacteria live and how they die through antibiotic attack; how genetic code is read and regulated; how intercellular forces control embryo development.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Rehabilitation Technology Co-creation Centre
Funder: Sir Jules Thorn Charitable Trust

Abstract: To provide enhancements to Rehabilitation Engineering laboratories to upscale rehabilitation options for the severely disabled.

Lay abstract: Patients with severe disabilities and impaired quality of life are surviving for longer. But there are insufficient NHS resources to support their physical rehabilitation. We will challenge this by developing our existing sector leading work in rehabilitation engineering through co-creation of innovative, user-friendly technologies to improve patients’ mobility which can be made widely available for independent use in the community. Our Rehabilitation Engineering team have developed novel prototype rehabilitation systems including intelligent treadmills, bikes and balance plates with immersive, interactive virtual reality programmes and motion capture technology not available elsewhere in the UK. This kit is unique in enabling real time bio- and visual feedback to aid recovery. While highly effective, the kit is not currently scalable and is only available to an extremely limited number of research patients. Our Rehabilitation Technology Co-creation Centre will involve rehabilitation users, commercial equipment providers, NHS and leisure centre partners. Jules Thorn funding will allow us, in a year, to 1) invest in more advanced rehabilitation equipment for a holistic treatment package 2) increase number of patients tenfold (from 5 to 50), whose feedback immediately informs future iterations of the technology and treatment plans 3) create a coherent suite of adapted user friendly and cost effective systems for community or home use, reducing reliance on trained staff (e.g. physiotherapists), consequently making effective rehabilitation more accessible 4) develop a new, more effective rehabilitation treatment model for mobility impaired patients for use in the community Advanced technology alone is not sufficient to help patients at large. Our co-creation approach relies on understanding how patients interact with the equipment to both improve its design, and present an attractive, accessible, manageable and effective programme of rehabilitation based on its use.

Research activity codes: 7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Fakes, Fabrications and Falsehoods? Interrogating the social, ethical and political features of pseudo-global health
Funder: Wellcome Trust

Abstract: A new phenomenon appears to be emerging in the enterprise of global health: a blurring between ‘real’ and ‘fake’ in a number of its key goals. In different geographical locations, the same object can be simultaneously regarded as both ‘real’ (i.e. certified and authentic) and ‘fake’ (i.e. uncertified and inauthentic). The vision of this research is to explore, using everyday examples, how this paradox is possible. A number of interconnected projects and inter-disciplinary methodologies are proposed to investigate two key goals in global health which are: knowledge production and access to drugs and medicines. Within these key goals, illustrative case studies from areas simultaneously considered real and fake will be explored as examples of ‘pseudo-global health’ and this concept will be assessed for its analytic potential. This research seeks to directly engage in the areas of ambiguity in global health to further understand how uncertainty and moral paradoxes are reconciled in practice. This necessitates a focus on the operations of global health at different; scales (global online networks and frontline field-level experiences), locations (e.g. contexts in the global north and south) and actors to capture the lived experiences and the structural factors which shape this phenomenon.

Lay abstract: A new phenomenon appears to be emerging in the enterprise of global health (GH): a blurring between ‘real’ and ‘fake’ in some of its key goals. In different geographical locations, the same object can be regarded as both ‘real’ (i.e. certified and authentic) and ‘fake’ (i.e. uncertified and inauthentic). This research will explore, using everyday examples, how this paradox is possible. A number of related projects and methods are proposed to investigate two key goals in GH which are: knowledge production and access to drugs and medicines. Within these key goals, illustrative case studies from areas simultaneously considered real and fake will be explored as examples of ‘pseudo-global health' to further understand how uncertainty and moral paradoxes are reconciled in practice. This necessitates a focus on the operations of GH at different; scales, locations and actors to capture the experiences and the structural factors which shape this phenomenon.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Elucidating the mechanisms of centromere protection and disjunction in genome stability maintenance
Funder: Wellcome Trust

Abstract: Chromosome segregation is essential for the accurate transmission of genetic material but is also a vulnerable process that can introduce genome instability. To segregate chromosomes perfectly, sister chromatids need to remain cohesed by the cohesin complex until stable spindle-kinetochore attachments are formed at the centromere to complete chromosome biorientation. Emerging evidence shows that to accurately disjoin sister chromatids following cohesin cleavage, cells require a specific chromatin modifying machinery comprising the PICH DNA translocase and the BLM helicase plus its partners. This complex resolves sister-DNA intertwinements that manifest as ultrafine DNA bridges (UFBs) in anaphase. Recently, we discovered that this machinery (named the UFB-complex) possesses a dechromatinisation activity that, when a key mitotic kinase, Polo-like kinase 1 (PLK1) is inactivated, can rupture centromeres during chromosome biorientation in metaphase. Since the UFB-complex is proposed to function during sister-chromatid disjunction, our findings imply that the UFB-complex is highly controlled to ensure centromere integrity throughout mitosis. In this proposal, I aim to elucidate the novel centromere-protection function of PLK1, particularly how it regulates the UFB-complex during mitosis. Additionally, I will investigate how the centromere damage caused by UFB-complex malfunction drives the evolution of whole-chromosome arm rearrangements and cellular transformation.

Lay abstract: To preserve our genetic material, DNA needs to be accurately duplicated and partitioned into the two daughter cells. The partition process is called "chromosome segregation" and is achieved through pulling one of the two paired chromosomes, at a specialised chromosomal region called a "centromere", into each daughter cell. Defects in centromeres therefore pose serious threats to chromosome segregation and have important implications for human genetic disorders and diseases. We aim to understand centromere organisation and regulation during chromosome segregation. Our team employs genetic and biochemical approaches to study the functions of a candidate DNA modifying complex in this process. We also use advanced imaging and cytogenetic techniques to observe how centromeres and chromosomes change when we interfere with this complex in human cells. Our work will lead to a better understanding of the origin of genome instability-related diseases (e.g. cancer), which will benefit the development of preventive and treatment therapies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Shame and Medicine
Funder: Wellcome Trust

Abstract: Shame is a powerful force in the everyday experiences of patients, medical students and healthcare practitioners. For patients, shame has been associated with treatment avoidance, increased burden of illness, and negative health outcomes, while also being recognised as a force that can sometimes motivate positive changes to lifestyle and health. Shame can influence how healthcare practitioners perform, interact with patients and other professionals, and cope with adversity. In addition, shame has been identified as a negative, yet frequently present, aspect of medical education. Despite the prevalence and significance of shame within various aspects of healthcare, at present, our understanding of the impact of shame, its many varieties, and other related negative self-conscious emotions, within medical contexts is incomplete. Shame and Medicine engages an interdisciplinary team working across medicine, medical humanities, and social sciences, in order to investigate shame, and related experiences, within healthcare. We aim produce new evidence on the experiential basis of shame, cultures of shame, and to investigate differential experiences of shame due to race, ethnicity, class and gender. Shame and Medicine is a ground-breaking interdisciplinary project that will propose new opportunities to improve the quality of healthcare delivery within a more responsive and effective health service.

Lay abstract: Shame is a powerful force in the everyday experiences of patients, medical students, doctors and other healthcare professionals. For patients, shame can lead to avoiding treatment, concealing illness and worse experiences of illness. Shame influences how doctors interact with their patients, and their colleagues, and is related to burn out, suicide and mental health problems. Despite repeated suggestions that shame plays a significant role in medicine, our current knowledge is limited. To address this, Shame and Medicine has a team of researchers working in medicine, the medical humanities and the social sciences. They will investigate the philosophy and cultural representation of shame in medicine, while also doing empirical studies looking at shame experiences in current healthcare practices and professional culture, in particular investigating how race, ethnicity, class and gender impact on the experience of medical shame. Shame and Medicine will provide evidence that will improve the quality of health services.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: The FAIRsharing service: supporting the research life-cycle
Funder: Wellcome Trust

Abstract: The use of repositories (for datasets, code and other research outputs), tools (for the annotation or analysis of data) and standards (for reporting, citing and identifying research outputs) are vital for high-quality, reproducible research and for the integrative analysis and comparison of heterogeneous data from multiple sources, domains and disciplines. To assist the virtuous research cycle, it is imperative that when resources are mature and widely adopted by the community, they are made discoverable by their producers, and channelled to the appropriate stakeholder consumer community, who in turn will use or recommend them (in policies and guidelines), or embed them into training material. Building on the success of the existing pilot 'portal', part of the ELIXIR Uk Node, and leveraging on its extensive network, we propose to deliver FAIRsharing as a community-driven, web-based, curated 'service' that both informs and guides the community on the evolving landscape of thousands of resources that are relevant to the research life cycle, specifically: repositories, tools and community standards, as well as journal and funder data policies that increasingly recommend these resources. Dedicated funds are needed to review, expand and future-proof the current organically-grown code, and to integrate the system with other international open portals.

Lay abstract: The uptake of repositories (for datasets, code and other research outputs), tools (for data annotation or analysis) and standards (for reporting, citing and identifying outputs) are vital for high-quality reproducible research. Whilst search engines, like Google, barely enable discoverability, we propose to build a community-level service to help: Researchers to find repositories, tools, standards that meet their funder requirements and needs for a data management plan; ensure that their shared data is reusable to increase their citations and subsequent benefits. Developers and curators of repositories, tools, standards to ensure their products can be evaluated and recommended by journals and funders; or reused and/or extended by other developers and curators, according to the products’ licence. Librarians to support scholars to utilize standards; conform to journal, institutional, and funder policies; develop and maintain institutional data repositories. Publishers and funders to gain knowledge of the evolving landscape of community-driven resources, refining their recommendations.

Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Addressing Health: Morbidity, Mortality and Occupational Health in the Victorian and Edwardian Post Office
Funder: Wellcome Trust

Abstract: This project will make a fundamental contribution to explaining the epidemiological transition in nineteenth and early twentieth-century Britain by analysing patterns of ill health derived from approximately 30,000 pension records of General Post Office (GPO) workers. Most postal workers in this period, particularly in London and large cities, retired early because of ill health. Sickness rates were higher in these places and rose over the period. We will use information on sickness and the reason for retirement to identify and explain spatial and temporal variations in ill health between 1859 and 1908. We will map ill health in different areas and in different types of places by analysing variations in sickness, taking into account geography, age, gender and occupation. We will use record linkage to identify the post-retirement life course for a sample of workers, providing an insight to the relationships between morbidity and mortality. We will examine policy responses relating to occupational health including medical provision, the design of workplaces, management of labour processes, and the implementation of technology. We will engage the public through an exhibition, website and freely available database that will be of major importance to family historians.

Lay abstract: In the late nineteenth and early twentieth century, Britain and other western countries witnessed a fall in mortality but a rise in sickness rates. This is called the epidemiological transition. We will explore the pattern of sickness during this transition by using a set of records created by the General Post Office that note the health of postal workers. The GPO was an extremely important employer in nineteenth and twentieth-century Britain. However, its workforce had relatively high rates of sickness and many workers retired prematurely because of illness. We will identify geographical differences in the incidence of ill health and for a sample of workers we will identify the ultimate cause of death. By doing this we will understand better the day-to-day experience of ill health in the workforce. We will also explain how the GPO responded to these problems by exploring the provision of medical care and other interventions.

Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE