NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of a Photoreactor for Solid phase Synthesis of Molecularly Imprinted Polymer Nanoparticles.
Funder: Wellcome Trust

Abstract: Over the last ten years Molecularly Imprinted Polymers (MIPs) have become an important research target as well as an instrument for solving industrial needs in separation and sensing. The work, however, is hindered by the poor processability of bulk MIP materials which cannot be easily integrated with sensors and assays and the polyclonal nature of the binding sites in materials synthesised using traditional approaches. These problems will be solved by developing solid-phase photoreactor which combines nanoparticle synthesis with affinity separation; the product of this process is comparable to natural monoclonal antibodies. The envisaged protocol includes synthesis of imprinted nanoparticles on solid supports with immobilised target molecule (template) which will double as affinity support for selection of high-affinity particles. This unique process has the added advantage of easy automation/scale-up. Currently there is no device available on the market for the production of MIP nanoparticles in the quality and quantities required by industry. Our main goal is to produce a working prototype synthesiser for industrial application based on the process described above and optimise its operational parameters for demonstration of its functional properties and market potential.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE;DISPUTED AETIOLOGY AND OTHER
Title: Consent Methods in Paediatric Emergency Medicine and Urgent Care Trials .
Funder: Wellcome Trust

Abstract: Clinical trials are needed to ensure that future treatments for seriously ill children are proven to work. However, if a trial fails to recruit enough children it may be closed, leaving health practitioners no choice but to give children unproven treatments. Guidance is therefore needed to assist doctors and nurses in recruiting to children s clinical trials and to address considerable confusion and apprehension about how to seek consent in the emergency care situation. It will provide guidance for doctors, nurses and researchers on how best to seek consent from families for seriously ill children to enter clinical trials in the emergency care setting. It will aim to improve the recruitment and consent process by examining people s experiences and views of consent in an emergency care trial. It will combine this knowledge on how recruitment does take place with knowledge from ethical principles on how recruitment should take place to develop guidelines to assist those involved in p lanning and conducting trials of treatments for critically ill children. The guidance and findings that the project produces will be circulated widely to relevant communities including funding bodies, researchers, children and families, clinical practitioners, ethics committees and bodies responsible for clinical research training.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;DISPUTED AETIOLOGY AND OTHER
Title: Commercial use of tissue samples in the 1958 birth cohort: A study of participants' views
Funder: Wellcome Trust

Abstract: To characterise the views of a sample of participants in the 1958 Birth Cohort on possible commercial uses of donated blood samples and to consider the legitimacy and legality of allowing such use within the terms of the original consent. More specifically, the aims of study are: To explore participants' understandings of the statements in the 1958 birth cohort information sheets to the effect that 'samples will be used for non-commercial research purposes only' and that use will be for 'future medical studies'. To identify whether participants' views are likely to vary depending on the type of commercial use proposed or the type of organisation seeking access to the resource;Explore participants' views on the value of creating a Participants' Panel to provide a forum for consulting participants on ethical,legal and scientific issues in the future To explore participants' understandings of the statements in the 1958 birth cohort consent documentation to the effect that information and samples will be used solely 'for use in future medical research studies of the causes, diagnosis, treatment or outcome of disease'. Identify a range of other commercial use clauses or principles seen as "protective" or "restrictive" or "useful compromises" by cohort owners, RECs, and industry, and explore participants? views of these To consider whether commercial access might be tolerated and lawfully granted under the existing consent and/or whether a reconsent procedure would be required for commercial use. Consult with a small number of key stakeholders, including Research Ethics Committees, the UKBB Ethics and Governance Council, and a small number of commercial firms to identify any further challenges or questions in relation to possible commercial use of tissue.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;DISPUTED AETIOLOGY AND OTHER
Title: Judging Best Interests in Paediatric Intensive Care: The Location, Basis & Scope of Decision-Making (BIPIC).
Funder: Wellcome Trust

Abstract: This study will examine the theory and practice of making decisions about the best interests of children in the paediatric intensive care unit in order to refine current theory and make practical recommendations. By examining the theoretical literature and then examining the moral experiences of key groups involved in deciding the best interests of children (parents, doctors, nurses,ethics advisory committees), using interviews considering common dilemmas where doctors may propose to withdraw treatment from very sick children, the study will reveal what these key groups mean by best interests and the degree to which the ideas of these different groups are compatible. Scrutinising practice may reveal new and unexplored problems or solutions and special attention will be paid to the possibilities for reaching consensual agreement in situations where there is initially serious dispute about what is best for the child. The information gained from the interviews will be combined with existing theory and used to devise an understanding that is better suited to what happens in reality. This will lead to recommendations about how these situations should be approached in future, with the aim of improving the way disputes are handled and the quality of the decisions that are reached.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;DISPUTED AETIOLOGY AND OTHER
Title: Exploring how laboratory animal technicians put ethics into practice.
Funder: Wellcome Trust

Abstract: We, Beth Greenhough (PI) and Emma Roe (Co-I), want to study whether animal experimentation procedures can be refined through developing greater understanding of the work of animal technicians (ATs) and the bodily skills and capacities they use in turning ethical principles into caring practices. Through preliminary meetings and interviews we have established collaborations with three Biological Services Units at Cardiff University, the University of Southampton and Queen Mary University of London. The research will involve eighteen in-depth interviews with laboratory ATs at these three sites as well as a two week period of ethnographic observation of ATs at work at one site and participant observation at the Institute of Animal Technology annual congress. This methodology has previously been used successfully by Roe in her work on farm animal welfare. The findings will be disseminated through attendance at the IAT annual congress, at least one academic research paper and a 10,000 word report for industry. This study will benefit laboratory animal research and facility staff, ethical review bodies and animals themselves by highlighting the role of the AT-animal relationship in ensuring good animal welfare and providing recommendations for supporting ATs in facilitating good animal welfare and contributing more fully in ethical discussions.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;DISPUTED AETIOLOGY AND OTHER
Title: The epithelial junction protein MarvelD3 in cell proliferation and migration
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Epithelial cells adhere to each other via junctional complexes, enabling them to form cellular barriers that separate different tissues and body compartments. These adhesive complexes transmit signals to the cell interior to guide gene expression and cellular processes such as proliferation and migration. Tight junctions are one type of intercellular junctions and restrict paracellular permeability. They are also thought to signal to the cell interior and several signal transduction pathways have been identified that are regulated by tight junctions. However, we know little about how plasma membrane components of tight junctions contribute to the regulation of the junction-associated signalling mechanisms and about the importance of such mechanisms for developmental processes. This proposal focuses on MarvelD3, a recently discovered transmembrane protein of tight junctions. Our preliminary data indicate that MarvelD3 signalling regulates cell proliferation and migration. At least in part, this involves regulation of specific signal transduction mechanisms Our aims are to identify molecular mechanisms by which MarvelD3 signals, to determine the role of MarvelD3 in a developmental model, and to test whether MarvelD3 signalling can be targeted to improve the quality of corneas donated for transplantation. The expected results will be important for the understanding of how cell-cell adhesion guides epithelial behaviour and to develop possible therapeutic strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;EYE
Title: Characterisation of LaNt regulation of Basement Membrane organisation in wound repair and angiogenesis.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The LaNts are a recently identified family of ECM proteins which preliminary studies have demonstrated to be important for cell-matrix attachment and cell migration. Based on their conserved domain architecture, the LaNts are hypothesised to elicit these effects through binding to laminins in the ECM and modulating their assembly into higher-order networks. In turn, these LaNt mediated changes in matrix organisation are predicted to directly influence cell behaviour supported by those substrates. To test these hypotheses, and to tease out the contribution of different aspects of LaNt biology to these processes, this proposal will use a combination of purified protein studies, cultured cells and finally three dimensional model systems to investigate LaNt roles in BM formation and organisation. Initially biochemical analyses will be used to identify and characterise LaNt - laminin interactions as well as LaNt interactions with other ECM proteins, and to determine the impact of LaNts upon laminin polymer formation. In the second part, epithelial and endothelial cells in culture will be used to analyse LaNt modulated matrix changes and to determine their impact on cellular functions such as proliferation, attachment and migration. Further mechanistic insight will be garnered through analysis of adhesion complex assembly, dynamics and ability to generate forces. Finally, tissue equivalent model systems of skin, cornea, limbal outgrowth and angiogenesis will be used to assess LaNt roles in more complex but also more physiologically relevant settings. The results garnered from these studies are likely to have widespread implications in expanding the understanding of processes associated with human biology and disease progression, for example the regulation of wound repair, tumour invasion and metastasis, in tissue morphogenesis and for processes involved in angiogenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;EYE;CARDIOVASCULAR;SKIN
Title: The mechanisms of photoreceptor cell death
Funder: Wellcome Trust

Abstract: Problems of protein homeostasis (proteostasis) that lead to protein misfolding, improper traffic and aggregation are associated with many forms of neurodegeneration. The neurodegeneration retinitis pigmentosa (RP) offers an excellent paradigm to study why proteostasis is critical for neuronal function and survival. Rhodopsin mutations cause dominant RP and disturb proteostasis, yet the underlying disease mechanisms and effective therapies remain elusive. I will exploit recent advances in gene editing technology and stem cell biology to produce new animal and patient derived models of the most common rhodopsin mutations in the UK. I will use these to address my key goals, i) to define any common disease mechanisms between the different classes of mutation, and ii) identify new therapeutic approaches for rhodopsin RP. I will use a combination of genetic and chemical manipulation of the major cell stress and degradation pathways, and identify the partner proteins of rhodopsin mutants using unbiased proteomic analyses. These complementary studies will be based on a series of interlinked hypotheses to determine how rhodopsin mutations disturb protein homeostasis and if this can be restored. The findings will have broader implications not only for other forms of retinal degeneration, but also neurodegenerative disease where proteostasis is disturbed.

Lay abstract: Vision is our most precious sense and it is important to understand what happens when vision fails so that we can develop new treatments. Inherited changes in the rhodopsin gene are the most common cause of the retinal dystrophy, retinitis pigmentosa (RP). Rhodopsin RP shares some features with other diseases like Alzheimer’s, Parkinson’s and Huntington’s disease where nerve cells die because the disease associated genetic changes lead to problems of faulty proteins upsetting the balance within nerve cells. In this research programme we will study the inherited changes that cause rhodopsin RP in the UK and define why they lead to blindness. We will do this using model organisms and also by using patient cells to make artificial retinas in the laboratory. We will then use this understanding to test a range of new therapies for this currently untreatable disease. These therapies could be used individually or in combination to help delay the progression of RP and extend useful vision. The understanding we develop could also be helpful to understand other types of neurodegeneration.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;EYE;NEUROLOGICAL
Title: Mouse Models of Human Variation and Disease
Funder: Medical Research Council

Abstract: 1. Mouse Models of Eye Disease. We study a mouse mutant line which lacks the, Fam151b gene and as a consequence has very rapid photoreceptor degeneration. Fam151b encodes a protein of unknown function, with similarity to glycerophosphodiester phosphodiesterases. We aim to identify the function of the FAM151B protein and understand the basis of the photoreceptor degeneration. We are in addition making mouse models of retinal detachment, by editing changes in mice into genes identified in genome wide association studies (GWAS) of Scottish populations. Analysis of the impact of these genetic changes on retinal histopathology and function will validate the gene identification from the GWAS. These studies will furthermore aid the understanding of the biology of normal retinal function and may indicate therapeutic avenues. 2. Understanding the Genetic Basis of Hair Colour Variation, We have performed a GWAS of several hundred thousand individuals in the UK Biobank, and identified many loci affecting hair colour. We are editing genetic changes in the genomes of mice, melanocytes and keratinocytes in order to determine the effect of these variants on gene expression, cell biology and mouse phenotype. Hair colour variation is an excellent example of a phenotype under complex genetic control. The cells and cellular interactions involved are well understood, and the genotype to phenotype connections are potentially tractable. It serves as a model for more diseases where there may be environmental as well as genetic effects, and where the cell types involved may be not well known or be less accessible.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;EYE;SKIN
Title: Preventing Healthcare Related Norovirus Outbreaks and Ward Closures through Identification of Reservoirs in Healthcare Settings: Viral, Host, and Environmental Determinants
Funder: Department of Health (England)

Abstract: Norovius outbreaks continue to increase dramatically worldwide and cause significant morbidity to patients and cost within the NHS; however relatively little is known about how norovirus is maintained within populations. The objectives of this study are to determine viral, human, and environmental factors that result in symptom-free and prolonged shedding of norovirus in order to inform new policies and methods for prevention of norovirus outbreaks. Clinical and molecular epidemiologic analyses will be used to identify factors that will greatly increase prevention opportunities. Findings will dramatically reduce the cost of NoV prevention in healthcare settings and increase patient safety.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: The Multicorder
Funder: Engineering and Physical Sciences Research Council

Abstract: We propose to create the world's first broad spectrum sensor technology - the Multi-Corder. We will do this by exploiting and advancing leading-edge microelectronic engineering. The world of electronics is dominated by complementary metal oxide semiconductor (CMOS) technology. CMOS has made modern computing and communications possible and has also made an enormous impact on sensing technology such as the digital camera chip. Most recently CMOS has enable the development of the personal genome machine - a next generation sequencing system. We propose to create technology to sense the personal metabolome. This is important since where the genome may indicate an individual's propensity towards a disease, the metabalome is an immediate measurement of body function, hence provides a means of diagnose. Not all possible afflictions are measurable using the metabalome. Using the same fundamental technology we also propose to detect microbial infectious agents. Bacterial affliction already in the body, or in the environment (e.g. a hospital ward) will be targetted, alleviating major problems such as hospital acquired infection. Further beneficiaries are in point of use diagnostic tools and highly portable systems capable of use in the developing world where there is limited infrastructural support. We also foresee yet more ambitious outcomes from the research, and we expect to made progress towards their realisation. We envisage that once a full measurement and analysis of a patient or a contaminated area is achieved, the Multi-Corder technology will underpin new methods of chemical synthesis for drugs. We will demonstrate the use of the technology for direct, high-speed, visualisation of chemical activity, and the means by which the data can be used to control the chemical process required for synthesis. The targets that we will address will take advantage of the ability of microelectronics to make many (millions if needs be) of devices on a single chip, or to integrate diverse technologies together. The core semiconductor technology will be augmented by chemical, lithographic and bio-technologies in order to build complex functions. Our approach is based on a combination of established track record, new insights, and emergent technologies for which we have established trial feasibility. Using our current knowledge as a springboard, we will exploit the flexibility and collaborative framework that a Programme Grant will afford us to create an exciting new technology.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Human and viral Golgi anti-apoptotic protein (GAAP); a structural and functional study of its mechanism of action
Funder: Medical Research Council

Abstract: A new inhibitor of apoptosis was discovered in camelpox virus and some strains of vaccinia virus (VACV) that has a very closely related protein (73% aa identity) in humans. The human and viral proteins have 7 transmembrane domains, are resident in the Golgi and inhibit apoptosis in response to a wide range of pro-apoptotic stimuli. They have been called v-GAAP and h-GAAP for viral and human Golgi anti-apoptotic protein. Closely related proteins are present across eukaryotes implying an ancient and conserved function. Functional analyses have shown that the human protein is expressed in all human tissues and is essential for cell viability. When h-GAAP is knocked down by siRNA cells die by apoptosis, and conversely, over-expression renders cells resistant to apoptosis. h-GAAP is also dys-regulated in many human cancers. v-GAAP is non-essential for virus replication, but affects the outcome of infection in vivo. Unpublished data indicate that h-GAAP and v-GAAP bind to the inositol 1,4,5-triphosphate receptor (IP3R) and modulate the release of intracellular calcium. This project concerns i) the structure and mechanism of action of h-GAAP and v-GAAP, and ii) the contribution of v-GAAP to inhibition of apoptosis by VACV that expresses other anti-apoptotic proteins. The study of h- and v-GAAP provides an opportunity to study the role of the Golgi in sensing pro-apoptotic stimuli and how modulation of the IP3R leads to alterations in intracellular calcium and resistance to apoptosis. Golgi proteins that regulate apoptosis are rare and so we intend to map the functional domains of h- and v-GAAP to determine if a) Golgi localisation and b) interaction with IP3R are required for their anti-apoptotic ability. The lack of v-GAAP in uninfected cells makes it ideal for analysis. We will continue to study h-GAAP because viral proteins often have subtle differences from their cellular counterparts and h-GAAP is clearly a key regulator of mammalian cell death. In addition, we will determine the structure of h-GAAP and v-GAAP and investigate if h-GAAP or v-GAAP can form a membrane pore. In parallel, we will obtain a transgenic mouse lacking mouse GAAP to study the role of m-GAAP in development and if GAAP-/- mice are viable they may also be valuable for studying the contribution of GAAP to development of cancer. An increased understanding of how IP3R function and calcium mobilisation are controlled and how this influences apoptosis is very important to many cellular processes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION