NIHRDataInsights/HRCSData huggingface dataset:
Title: A Chemical Technology to Generate Homogeneous Antibody-drug-Conjugates (ADCs) and Bispecifics
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Using antibodies as therapeutics and diagnostics is one of the most promising areas of research into new healthcare products. Antibodies represent the fastest growing class of therapeutics, with over 20 approved for clinical use to date and over 150 in clinical development. It is estimated that the global market for antibody therapeutics is currently around $50 billion. Two particularly promising classes of antibody based therapeutics are antibody-drug-conjugates (ADCs) and bispecifics, commonly referred to as 'magic-bullet' therapies due to their ability to seek and destroy just diseased cells within the body (e.g. cancer cells). However, a major hindrance to the area is the lack of suitable chemical methods for the construction of homogeneous, well defined, antibody conjugates. Here we propose to exemplify a powerful new chemical technology that we have developed to overcome these limitations, to enable the design of superior next generation ADCs and bispecifics.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Unlocking the complement-suppressing potential of factor H with a bacterial polypeptide
Funder: Biotechnology and Biological Sciences Research Council

Abstract: A challenge in medicine is that contact between blood and manmade devices (such as intra-vascular stents used in cardiac surgery or dialysis equipment for kidney-failure patients) can trigger part of the human immune system called the complement cascade, with dire clinical consequences. We discovered that PspCN, a polypeptide of microbial origin, "turbocharges" a human protein (CFH) that inhibits the complement cascade. Guided by the results of a market assessment, we now propose to design, manufacture and test PspCN-decorated surface coatings for medical implants. We aim to demonstrate that the PspCN displayed on these potentially protective coatings will grab hold of CFH, which is abundant in blood, and induce the captured CFH to switch from a latent to an activated form. Thus, in an improvement on the efforts of competitors to utilize CFH in its latent form, our approach will afford coated surfaces that are protected from the complement cascade by the patient's own, activated, CFH.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: 13 ERA IB TERPENOSOME: Engineered compartments for monoterpenoid production using synthetic biology
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Terpenoids are commercially valuable natural fine chemicals with a variety of uses as drugs (taxol, artemisinin), nutraceuticals (carotenoids), cosmetics (astaxanthin), and agriculturals (gibberellins). Monoterpenoids are mainly produced in plants and are used as flavours (e.g. limonene), and fragrances (e.g. carveol), as well as precursors for pharmaceutical molecules. However, the natural production of commercially relevant monoterpenes is limited, since their extraction from plants is costly and inefficient, and the alternative chemical synthesis involves long and complex, multi-step protocols. Monoterpenes produced from bacteria using heterologous biosynthesis pathways would be ideal for sustainability and compound diversity; however, so far it has produced low yields, while sesquiterpenes have been successfully overproduced by, e.g., Martin and coworkers (2003, Nature Biotech 21:796-802). TERPENOSOME will develop yeast and bacterial monoterpenoid producing strains using synthetic biology approaches, which bypass many of the production constraints associated with chemical synthesis and isolation from natural resources. Metabolosomes are recently discovered bacterial organelles, which are large structures composed of an exterior protein shell with multiple enzymes compartmentalised on the inside. There are currently only two examples reported in the literature for the localisation of green fluorescent protein inside ethanolamine utilization metabolosomes (Choudhary et al., 2012). These serve as excellent proof-of-concept examples to show: (1) that non-native proteins can be targeted inside metabolosomes, and (2) that metabolosomes can be used as closed scaffolds inside host organisms TERPENOSOME will be the first to apply the metabolosome to synthetically designed monoterpene biosynthesis for production improvement, side product reduction through improved metabolic control and higher local flux, and to avoid toxicity limiting production levels.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: THE ROLE OF RAMPS IN LIGAND-ENGENDERED SIGNAL BIAS OF SECRETIN-LIKE RECEPTORS
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Receptor activity modifying proteins (RAMPs) are essential partners of the calcitonin and calcitonin receptor-like receptors, allowing them to respond to amylin, calcitonin gene-related peptide and adrenomedullin. These receptors are members of the family B G protein-coupled receptors (GPCRs). It has been suggested that at least seven other family B GPCRs can interact with RAMPs, but the consequences of these interactions have not been explored except for the corticotrophin-releasing factor (CRF) type-1 receptor and the VPAC1 and VPAC 2 receptors, where RAMPs alter G protein specificity and agonist bias. For the CRFR1, RAMP2 association enhances the ability of the receptor to promote ACTH release in vivo. Thus, RAMP association with family B GPCRs is widespread and is physiologically important. This has created an urgent need to fully characterise the extent and consequences of these interactions and to properly understand the pharmacology of these important drug targets. The native pattern of GPCR coupling to G proteins is preserved in yeast engineered with mammalian-like G proteins and we have shown that this system can be modulated by RAMP co-expression. This provides the basis of a high-throughput assay to investigate the effects of RAMPs on G protein coupling and agonist bias. We will establish if RAMPs 1, 2 and 3 modulate receptor-G protein interactions for each of the 15 human family B GPCRs using multiple agonists for each receptor. This data will enable us to determine if each combination generates a specific signalling bias. We will continue these studies to investigate the consequences of the interactions using specific mammalian cell assays for RAMP-receptor interactions, agonist-stimulated G protein activation and second messenger regulation. Ultimately, the data we generate will form the basis of an extended study using animal models and will enable structural studies aimed at developing selective drugs for individual RAMP-receptor-G protein complexes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A BioImagingUK Network: A Scientific Community Defining Strategic Initiatives for UK BioImaging.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We have built BioImagingUK (http://bioimaginguk.org), a grassroots initiative to define strategic priorities, access policies, and sustainable practices for UK imaging science. That effort has built an aligned, committed consortium of imaging scientists and technologists who have contributed to a clear, public statement of strategy and policy for UK bioimaging.To date, BioImagingUK's activities include a series of community activities centred on organising our priorities, developing strategic statements, representing the interests of the UK bioimaging scientists, and coordinating UK's response to Euro-BioImaging's evolving activities and calls for proposals. Since our founding in 2009, we have:1. Held several open meetings of the UK bioimaging community to define actions, strategy and planning (http://bioimaginguk.org/index.php/Meetings_Page);2. Convened a meeting of >70 UK bioimaging scientists in July 2012, and released a public summary of the priorities the meeting defined, the BioImagingUK Strategy Meeting Summary (http://bioimaginguk.org/images/0/04/BioImagingUK_Meeting_Summary_v5.pdf);3. Presented the case for community-led strategic prioritization at several UK imaging meetings (e.g., http://www.rms.org.uk/events/pastevents/index/frontiersinbioimaging; http://www.rms.org.uk/Resources/Royal Microscopical Society/Events/fmm-2014-provisional-programme-7.pdf); 4. Represented the UK at Euro-BioImaging Stakeholder & Steering Committee Meetings (http://www.eurobioimaging.eu/content-page/united-kingdom; http://www.eurobioimaging.eu/content-page/euro-bioimaging-steering-committee) and coordinated submission of the UK's Expressions of Interest for Euro-BioImaging Nodes (http://www.eurobioimaging.eu/content-page/first-euro-bioimaging-open-call-nodes-parta-archive-information)This proposal seeks the first formal funding for BioImagingUK, to form a UK Network, that will be used to continue and expand BioImagingUK's activities.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: To map the organisation of nutrient signalling pathways
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We propose to begin to characterize the responses of freshly-prepared, collagenase-liberated isolated mouse hepatocytes to a range of specific nutrient challenges, that cannot be applied in vivo, in terms of their effect on the class I & III PI3K pathways to mTor, mTor activity, the intiation of autophagy and ROS production. So that in the second half of the project we can look at aged and diet-restricted animals. We aim to publish our first major study indicating that amino acids controlling mTor activity are taken-up by macro-pinocytosis and to have advanced our work addressing the nature of the Ca2+ signals controlling mTor at lysosomes near to a point of submission. We will have tested several amino acid analogues for their effect on mTORC1 activation and then image their distribution within cells. A project following-up the confirmed hits from our genome-wide screens for suppressors and activators of vps34 complexes in autophagy. This work will focus on specific hypotheses arising from that work using a combination of molecular, cell biology and systems approaches to assemble subsets of hits into meaningful regulatory networks. Within that project we aim to have isolated the subset of hits that appear to affect mTORC1 localization and activity and begun to generate a signalling diagram leading from starvation to autophagy. We will have begun to analyse the products of DAz-2 derivatised cell lysates to reveal the complexity of the samples we will be attempting to analyse. Following on from our new data we will define the activation status of ERK1/2, p38, MNK1/2 and eIF4E during nutrient starvation and during acute and chronic mTOR inhibition in primary human fibroblasts and assess their activation in young and aged fibroblasts. This will be a pre-requisite to gene expression studies and analysis of young and aged samples.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The effect of inter-individual variability in stress responses during ageing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Ageing was once regarded as a random and progressive decline, until ground-breaking work in the nematode Caenorhabditis elegans demonstrated that a number of pathways control longevity, including insulin signaling pathway. Despite been genetically controlled, life expectancy is variable in many organisms, including laboratory strains of C. elegans, that lack genetic variability. The ageing process is exquisitely sensitive to protein folding homeostasis in the cell and molecular chaperones, key targets of insulin signaling pathway, are pivotal to this process by refolding proteins misfolded by genetic and/or environmental stressors. Despite its essentiality, it has been shown that chaperone’s transcription is highly stochastic across species. Moreover, we have previously demonstrated that inter-individual variation in chaperone expression in C. elegans is a good predictor of both stress resistance and mutation penetrance. We think that part of the mechanism that leads to lifespan variability is related to the inter-individual variability of chaperones and other genes that modulate longevity. We are interested in understanding what are the causes underlying inter-individual variability in the longevity pathways. A clue comes from the observation that the level of chaperone expression is passed through at least one generation. Because trans-generational memory in adaptation is usually associated with epigenetic mechanisms, these new findings suggest that at least part of the variability is related to chromatin modifications. In addition, we are interested in using sophisticated statistical tools to develop early biomarkers that can perform as predictors of lifespan as well as health-span. We think that the questions that we are addressing will get us closer to understanding what makes us different as individuals and how these differences influence the way we age.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Multimorbidity: prevalence, risk factors and resilience in a large scottish birth
Funder: Chief Scientist Office (Scotland)

Abstract: Background: Multimorbidity, the coexistence of two or more chronic conditions, is a growing healthcare challenge. The aim of this research is to understand the prevalence of high burden multimorbidity (that which requires health service input) and the factors associated with both its development and resilience to its effects. Research questions 1: What is the prevalence of high burden multimorbidity and how does multimorbidity accumulate over time? 2: Which early and later life factors are important influences on the risk of multimorbidity in middle age and older age? 3: What proportion of those with multimorbidity are considered resilient and vulnerable and which early and later life factors are associated with this? 4: What are the long term outcomes for resilient and vulnerable individuals with multimorbidity? Method The Aberdeen Children of the 1950s cohort contains 12,150 individuals born between 1950-1956 who have been followed-up since 1962. There are multiple early life and later life variables as well as existing linkages to hospital administrative data. Novel linkages will be explored. Multimorbidity will be assessed using administrative data and resilience will be defined using the response to a questionnaire administered in 2001-03. Factors associated with the risk of developing multimorbidity or being resilient in the face of multimorbidity will be assessed using regression models. The long term outcomes for resilient and vulnerable individuals will be mortality and the degree of accumulation of multimorbidity. The findings can inform the development of sen/ices targeted towards multimorbidity and the development of interventions to reduce its impact.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Optomising pallative care for older people in the community: development and evaluation of a new short term collaborative service
Funder: Department of Health (England)

Abstract: Context: People are living longer and more and more die following a period of increased illness and symptoms Palliative care is advocated for older people to address this, but with little evidence of effectiveness. Short-term palliative care may be cost effective and appropriate because it relies primarily on existing community services, with additional shared support from palliative care services.


Research activity codes: 7.2 END OF LIFE CARE
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing stated preference discrete choice experiments for informing and improving the redesign of patient-led healthcare services
Funder: Department of Health (England)

Abstract: Objectives: Develop methodology and provide new policy-relevant information on preferences for facilitating delivery of patient-led healthcare reforms around place of death.Design: Use DCE and mixed-methods to investigate methodological issues, conduct empirical analyses, investigate BTA to generalise DCE results, disseminate, and build capacity.Expected outcomes: Refine methods and improve the quality of information that can be used to inform and target resources in the right places; increase policy-relevance of DCE; identify when costly new research studies can be avoided; increase DCE and awareness and competency in the wider research community and NHS.Anticipated benefits: Potential to deliver patient-focused services.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE
Title: Improving early phase clinical trials through integration of information from other stages and trials
Funder: Department of Health (England)

Abstract: The development of new medicinal products and health technologies is a time consuming and expensive process that often lasts 10-15 years and costs several hundred million pounds. The long duration is due to the extensive evaluations addressing different questions such as safety, dosing and efficacy that are necessary before a product is widely used. Among the largest contributors to both time and cost are confirmatory clinical trials that often involve thousands of patients with follow-up periods frequently lasting years. In recent years, however, an increasing number of confirmatory clinical trials have been unsuccessful exposing a large number of patients to ineffective or harmful treatments while at the same time costing substantial amounts of money. The reasons for these failed trials are generally thought to be taking forward treatments that should have been abandoned during early efficacy studies and insufficient precision in the early stages of the development; in particular when determining the maximum tolerated dose, assessment of safety or when determining the patient population to be studied further. The challenge therefore is to improve the early stages of development to eliminate ineffective or harmful treatments early in the development process which in consequence will reduce the number of unsuccessful confirmatory trials and result in safer and more efficient medical interventions overall. Based around collaborations with public sector medical research institutions, this research aims to identify specific projects lacking suitable existing methods and develop and implement novel early phase trial designs.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: The effectiveness and acceptability of financial incentives for encouraging uptake of health-promoting behaviours in the UK
Funder: Department of Health (England)

Abstract: Leading a healthy lifestyle can reduce the risk of developing a range of diseases. Giving financial rewards for healthy behaviours, or reducing the cost of these behaviours, is one way of encouraging people to live healthier lifestyles. This research will explore under what circumstances rewards and cost reductions for healthy behaviours are effective, and what the UK public thinks about this sort of scheme. The work will include a review of existing research, an evaluation of one reward programme, a study of what type of rewards people find most motivating, and a survey of UK opinions on these schemes. The results will be used to design effective and acceptable reward and cost reduction programmes to help people lead healthier lifestyles.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE
Title: Revalidation policy, in practice and the public
Funder: Department of Health (England)

Abstract: From December 2012, UK doctors are being asked to provide evidence that they are fit-to-practise on a five yearly cycle; called Revalidation. But Revalidation discussions started over 12 years ago and remains controversial. Revalidation is a complex intervention with a number of proposed purposes which are likely to have unintended as well as intended consequences. The programme of research seeks to better understand the meaning of Revalidation from stakeholders’ perspectives; policy makers, doctors, the wider health service and patients. The programme uses 3 different ways of analysing talk from interviews, focus groups and video-ed appraisals. By understanding the meaning and impact of Revalidation the research seeks to shape future implementation policy; maximising the potential positive while reducing the potential negative consequences, thus supporting future healthcare in the NHS.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: The Impact of Physician Incentives on Health Inequalities
Funder: Department of Health (England)

Abstract: The Impact of Physician Incentives on Health Inequalities In an attempt to improve the quality of care for patients, governments and health care funders worldwide have begun experimenting with incentives for physicians, offering financial rewards for the achievement of specified performance targets. In some cases incentives have led to improvements in quality of care, but concerns remain about the unintended consequences of incentives, for example that aspects of patient care that are not incentivized will be neglected. Incentive schemes can also benefit some groups of patients more than others, leading to an increase in health inequalities. The aims of this project are to gain a deeper understanding of the unintended consequences of physician incentive schemes and their effect on health inequalities, and to identify ways to promote more equitable health outcomes in future. The project will focus on incentive schemes operating in England and in the United States, and will examine variation in intended and unintended outcomes for different population groups. The impacts of incentives on physician behaviour and motivation will also be examined.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE
Title: Reducing short stay unplanned hospital admissions for acute illness in children
Funder: Department of Health (England)

Abstract: The number of children attending hospital emergency departments and being admitted to hospital for acute illness has increased in recent years. The aims of this project are to: 1) Explain what is driving the increase in attendances and hospital admissions in children 2) Examine solutions to the problem through new ways of delivering GP services and urgent care for children with acute illnessResults should help GP commissioners of care to safely reduce the number potentially avoidable short stay and frequent hospital admissions for acute illness in children, with benefits for children and families and better use of NHS resources.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE