NIHRDataInsights/HRCSData huggingface dataset:
Title: Health Impacts of urban Transformation (HIT) Consortium
Funder: Medical Research Council

Abstract: This grant is funded by the UK Prevention Research Partnership (UKPRP) which is administered by the Medical Research Council on behalf of the UKPRP’s 12 funding partners: British Heart Foundation; Cancer Research UK; Chief Scientist Office of the Scottish Government Health and Social Care Directorates; Engineering and Physical Sciences Research Council; Economic and Social Research Council; Health and Social Care Research and Development Division, Welsh Government; Health and Social Care Public Health Agency, Northern Ireland; Medical Research Council; Natural Environment Research Council; National Institute for Health Research; The Health Foundation; The Wellcome Trust. Cities are being transformed by an ensemble of powerful social, economic, behavioural and technological forces, presenting new challenges and opportunities to promote healthy living and disease prevention. The key challenge addressed by our consortium is to develop methods to understand, characterise and predict impacts of these multi-sectoral urban transformation processes, within a complex, highly dynamic and partially observed system. Our goal is the promotion of healthy living, improved health and reduction in health inequalities, by analysing well-understood pathways of influence and characterising new and emerging pathways. Our focus is on how changes in the urban environment affect, in children, i) lung function and lung growth (risk markers for chronic respiratory illness in later life) and ii) cognitive development; and iii) non-communicable diseases (NCDs) in adults, both city-wide and at small-area scale. Using London as an exemplar global city, we take a multi-disciplinary systems-wide modelling approach, combining leading data, modelling and application expertise in epidemiology, public health, behavioural, transport, physical activity, policy and urban systems modelling, with close involvement of diverse user community in planning, delivery, local authorities and public health. To ensure the project is practically grounded and produces policy relevant outputs, we combine fundamental work in modelling and analysis of health impact pathways in urban systems with two exemplar case studies. The first is the ultra-Low Emission Zone (uLEZ), a natural experiment implemented from April 2019, with expected major impact on levels of noise and air pollution. The second is the Old Oak Common/Park Royal Development, a major regeneration and transport hub project, offering the opportunity, with the user community, to have direct influence on its design and implementation to improve health. To complement and support the technical work of the project, we will put in place a programme of active user engagement in co-production, dissemination, translation and outreach.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: GENERIC HEALTH RELEVANCE;MENTAL HEALTH;NEUROLOGICAL;RESPIRATORY
Title: Improving UK breastfeeding duration:salutogenic evaluation of English regional success to codevelop community-based breastfeeding support intervention
Funder: Medical Research Council

Abstract: Background: Breastfeeding rates in the UK are some of the lowest in Europe. North Somerset has the highest breastfeeding rates in the UK, including within deprived areas, where rates are usually lower. Aim: to co-develop an affordable community-wide approach to supporting breastfeeding that maps out the resources, activities, and context required to enable women to breastfeed for longer, following MRC intervention development guidance. Design: Mixed methods evaluation of North Somerset breastfeeding context and intervention co-development with public health staff, breastfeeding peer supporters and mothers. Methods: The North Somerset context will be explored using: documentary analysis of policies and reports; descriptive analysis of quantitative service level data; individual interviews with local authority staff involved in service design and delivery; online focus group with breastfeeding peer supporters; urban ethnography of Weston-Super-Mare, the largest town in North Somerset; and a survey of mothers. Intervention co-development will take place through nine consultation events: three each with three groups of stakeholders (public health staff and breastfeeding peer supporters from North Somerset and mothers from around the UK). This will enable us to establish a list of essential elements; a self-assessment tool and toolkit of resources; and a suite of outcome measures for a future trial. Next steps: Following this intervention development study, we will seek funding for a feasibility trial with an inbuilt process evaluation to assess the feasibility of (i) utilising the toolkit in practice and (ii) research procedures and outcome measures necessary for a larger-scale effectiveness trial.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE;MENTAL HEALTH;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Healthy Lives - Malawi : Intergenerational Cohort of Chronic Conditions
Funder: Wellcome Trust

Abstract: Supported by public engagement experts, local organisations and creatives, MEIRU researchers will co-design and deliver three core public engagement activities (PEA) mapped to key research themes of the HLM and GM programmes. PEA1: Primary school engagement on early origins of long-term conditions Students will create dramatic, musical, oral and poster presentations exploring the role of their parents’ health and childhood environment on future health and wellbeing for sharing with their communities, District Management Teams and researchers to start community conversations about their influence on health. Y1 Creation, Y2/3 PresentationPartners: School Health and Nutrition programme, Schools, UNICEF. PEA2: Sharing voices of women and families affected by maternal mental health conditions Creation of a resource (audio and video vignettes) to make women’s narratives of maternal mental health visible in communities, policy discussions (presenting to the Reproductive Health Unit and Mental Health Technical Working Group) and international meetings to agenda set and impact policy. Y2 Creation, Y3/4 DisseminationPartners: African Alliance for Maternal Mental Health (AAMMH), St John of God Mental Health Services PEA3: Documenting family journeys and infant development in birth cohort families. Documentary style interviews, observations with families on repeat occasions during cohort follow-up, to include filming of cohort procedures and interviews about cohort membership as well as footage of child development and family aspirations, to give context and meaning to statistics on child and family health in Malawi. Y1 Recruitment, Y2-4 Filming, editing and disseminationPartners: Art and Global Health Centre Africa (www.artgloafrica.org), UNICEF, film makers


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE;MENTAL HEALTH;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Experiences of hospital admission in people with diabetes: what can we learn from users and carers to improve unscheduled inpatient care and to prevent unnecessary hospital admissions?
Funder: Department of Health (England)

Abstract: Typically, 10-25% of UK hospital beds are occupied by people with diabetes. Patient experience is often poor, length of stay prolonged, emergency readmissions increased and healthcare costs high. This poor experience and unnecessary financial burden is an obvious target for quality improvement by innovation. My aim is to explore experiences of people with diabetes admitted to hospital in a 6-month period (using taped, semi-structured interviews) to define problems with care, to find innovative solutions for better management and to evaluate effectiveness of these innovations. I will consider the whole patient pathway, not just the hospital episode, and I anticipate the remainder of the CAT research will address:1. Pre-hospital: (a) effectiveness of supported self-management; (b) access to timely support during intercurrent episodes; (c) appreciation of alternatives to hospital admission2. In hospital: (a) Diabetes specific issues; (b) generic unscheduled issues; (c) right place, right person; (d) effectiveness and timeliness of discharge3. Post-discharge: support for recovery and to prevent unnecessary emergency readmission.Improving unscheduled care will be invaluable locally and nationally to support QIPP.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: How are health care organisations dealing with the challenge of providing co-ordinated diabetes care in an increasingly diverse NHS?
Funder: Department of Health (England)

Abstract: This study is concerned with the effect of incentives for competition and collaboration on organisations' delivery of co-ordinated services. The research will use theoretical frameworks associated with inter-organisational relationships to inform case study research of two local health systems using qualitative and quantitative methods to explore the way healthcare organisations understand their objectives and negotiate relationships with other organisations to provide co-ordinated diabetic services. The research will increase understanding of how incentives affect delivery of co-ordinated care, including whether they can be combined to improve the co-ordination of care, which will be of use to policy makers and healthcare organisations.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Mitochondrial transport proteins in human physiology and disease
Funder: Medical Research Council

Abstract: Mitochondria play a central role in the utilisation of sugars, amino acids and fat by the human cell. Pathways, such as the citric acid cycle, aspartate-malate shuttle and fatty acid oxidation are used to drive the synthesis of ATP via oxidative phosphorylation. Mitochondria also carry out the synthesis and degradation of amino acids (urea cycle) and the synthesis of haem and iron-sulphur clusters. Mitochondria are able to replicate, transcribe and translate mitochondrial DNA. They are also involved in the generation of heat during thermoregulation by dissipation of the proton gradient through uncoupling proteins. Since the mitochondrial inner membrane is impermeable to small polar molecules, a large number of transport proteins are involved in their import and export. The mitochondrial carrier family is one of the major transport protein families and there are 53 different members in man, but only half of their functions are known. There are also other transporters active in mitochondria, such as the mitochondrial pyruvate carrier and ABC transporters, but there could be many others, as a large number of compounds need to traverse the membrane. We are interested in studying mitochondrial transport proteins not only because of their central role in metabolism and physiology, but also because of their involvement in metabolic and neuromuscular disorders, obesity and fever, making them potential targets for drug development. One area of our research is aimed at the identification of the remaining mitochondrial transporters to complete our understanding of their role in physiology and disease. Among the transported compounds are many key components of cellular metabolism, such as essential amino acids, co-factors, inorganic ions, nucleotides, and antioxidants. Another area of interest is the discovery of transport proteins that are involved in human disease. Many mutations of mitochondrial transport proteins lead to metabolic, neurological and muscular mitochondrial diseases and it is likely that more links will be discovered through exome sequencing. We would like to understand the transport process at the atomic level to explain why these diseases occur.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Mitochondrial Complex I
Funder: Medical Research Council

Abstract: Complex I (NADH:ubiquinone oxidoreductase) is crucial for respiration in many aerobic organisms. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and β-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force that powers ATP synthesis. It is also a major contributor to cellular production of reactive oxygen species (ROS). Complex I is linked to medicine on many different levels: from mutations in its subunits and assembly factors that cause mitochondrial diseases, through the production of reactive oxygen species and oxidative damage (which may be relevant to neurodegenerative diseases such as Parkinson’s disease), to complex I as a potential drug target in diabetes, ischaemia-reperfusion and cancer, and complex I-linked drug side effects. Understanding the functions and dysfunctions of complex I in these contexts is an intellectual and scientific challenge for both medical and basic scientists that must be tackled on multiple levels. Basic molecular knowledge of the enzyme’s structure and mechanism is required to provide a foundation for biomedical function-dysfunction studies of complex I in mitochondrial and cellular systems of greater complexity. The central thrust of the future work of the Mitochondrial Complex I group is to develop and apply structural and mechanistic knowledge about complex I, in order to answer questions about its role in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions. Thus, we are working toward a high resolution structure of the enyzme, developing model systems for the study of mutations in order to determine the enzyme mechanism and define the molecular-level reasons for genetic complex I dysfunctions, and working with material from rodent model systems and cultured cells to study complex I-related pathologies directly in mammalian cells. On multiple levels these studies also allow complex I-drug interactions to be evaluated as pharmocological mechanisms and the causes of side effects.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Mitochondrial Genetics
Funder: Medical Research Council

Abstract: Human mitochondria have their own genome (mtDNA) that is two hundred thousand times smaller that the nuclear genome (nDNA) and encodes only thirteen essential subunits of the oxidative phosphorylation (OXPHOS) machinery. Given the relatively small size of the mitochondrial genome our detailed understanding of the molecular mechanism that govern mitochondrial gene maintenance and expression is still surprisingly sketchy. Defects of mtDNA and nDNA are well-recognised cause of genetic disorders that have diverse clinical manifestations ranging from progressive muscle weakness to fatal infantile disease. Much of our understanding of mitochondrial molecular genetics has come from studying rare mitochondrial disorders. Currently there are no effective treatments for these diseases and there are very few animal models for them. The slow progress in gathering more data on how mitochondrial genome is regulated is, in large part, owing to our current inability to edit mtDNA. Genome engineering techniques, analogous to the ones routinely used to modify the nuclear DNA, are not in hand, so we are unable to interrogate the role of cis-acting elements for RNA expression as well as transcription or replication. Furthermore, we are still unable to introduce pathogenic mtDNA mutations at will so their effect could be studied in animal models. In particular, the programme focuses on: (i) Studying the basic mechanisms of mitochondrial genome regulation with the main focus on the novel proteins responsible for nuclolytic processing of precursor mitochondrial RNA, polyadenylation of mitochondrial messenger RNA, post-transcriptional nucleotide modification of mitochondrial RNA and mitoribosome biogenesis. (ii) The analysis of the key aspects of mitochondrial genome regulation in samples derived from patients affected with mitochondrial disease. This analysis is a source of valuable insights into the pathomechanisms of human disease, and also into basic mitochondrial molecular genetics. Importantly. They provide patients with a molecular diagnosis for prevention (prenatal genetic diagnosis) and counselling. (iii) Developing new approaches for the genetic modification of mitochondria of living cells. The key long-term aim is to establish routine methods of genetic modification of mammalian mitochondria. Enzymatic methods are being developed to modify the mitochondrial genome e.g. engineered zinc finger nucleases are delivered to mitochondria in order to deplete cells selectively of specific mtDNA variants.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Targeting the serotonergic pathway in humans to treat metabolic disease
Funder: Medical Research Council

Abstract: The continuing rise in the prevalence of obesity and associated metabolic disease highlights the need for new treatments. Pharmacotherapy for obesity has mainly focused on limiting food intake and been largely ineffective. An alternative approach is to increase energy expenditure and the recent identification of brown adipose tissue (BAT) in adult humans has highlighted the potential to activate BAT as a novel treatment for metabolic disease. However, most of our knowledge of BAT is based on data from rodents and we have recently identified substantial species-specific differences in the regulation of BAT activation. This underlines the need to study this physiology in humans to understand how to activate BAT as a novel therapeutic strategy. We have discovered high expression of the serotonin transporter (SERT) in human BAT and that inhibition of SERT enhances serotonin-induced suppression of human brown adipocyte activation. We will perform three separate in vivo experimental medicine and parallel in vitro studies to dissect serotonergic signalling in human BAT and determine whether manipulation of this pathway is a novel therapeutic strategy to treat metabolic disease. These studies will investigate 3 key aspects of this biology by inhibiting 1) the SERT transporter, 2) the serotonin receptor and 3) peripheral serotonin synthesis. To measure the effect on BAT activity and wider metabolism we will use a combination of in vivo techniques we have developed such as PET/MR scanning, thermal imaging, microdialysis, indirect calorimetry and stable isotope infusions and in vitro techniques such as primary human adipocyte culture, cell sorting and respirometry. In addition, we will develop an entirely novel in vivo technique using microdialysis to directly administer drugs to human BAT and quantify activation using PET/CT. This research may reveal a novel approach to treat obesity and associated metabolic disease by reducing peripheral serotonin action.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Molecular mechanisms of impaired glucose transport in insulin resistance
Funder: Medical Research Council

Abstract: Insulin resistance, a condition where the hormone insulin no longer efficiently lowers blood glucose, is a risk factor for the development of type 2 diabetes, and is also linked to development of cardiovascular disease, some cancers and neurodegenerative diseases. Insulin promotes glucose uptake into adipose and muscle tissue through the redistribution of the glucose transporter GLUT4 from intracellular stores to the cell surface. This process is defective in insulin resistance. The overall aim of my fellowship is reveal the molecular mechanisms for impaired insulin-stimulated GLUT4 trafficking in insulin resistance. This comprises three specific aims. First, I will use proteomics and develop a high-throughput screening platform to find changes in protein localisation and/or protein expression that contribute to impaired GLUT4 trafficking in insulin resistance. Second, I will use microscopy techniques and trafficking assays to study the how the protein TRARG1, a recently identified regulator of GLUT4 trafficking, controls GLUT4 trafficking and whether impaired in signalling to TRARG1 plays a role in insulin resistance. Finally, I will follow up on my recent work that supports a key role for reactive oxygen species in mitochondria in insulin resistance by using phospho- and redox proteomics to map the pathway that connects mitochondrial reactive oxygen species to impaired GLUT4 trafficking in the cytosol. These studies have potential to reveal new information on how insulin regulates GLUT4 trafficking in health, and how this process becomes defective in insulin resistance. These studies may reveal rational therapeutic options for correcting glucose transport in insulin resistance. This is significant since there are currently no medications for type 2 diabetics that target glucose transport to aid glycaemic control. In the longer term, such medications may help alleviate the development of type 2 diabetes and burden of other insulin resistance-associated disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Biochemical investigation into the regulation and molecular mechanism of CHC22 clathrin
Funder: Wellcome Trust

Abstract: Clathrin is a self-assembling protein that forms a basket to move cargo between different compartments within cells. One type of clathrin, CHC22, is prominently expressed in muscle and fat cells and moves a sugar (glucose) transporter called GLUT4 to a specialised intracellular location, where it is kept during fasting. When insulin is produced after a meal, it stimulates movement of GLUT4 to the surface of muscle and fat cells to import glucose from the blood for energy or storage. This process is disrupted in Type 2 diabetes (T2D), resulting in a mislocalisation of CHC22 and a dysregulation of glucose metabolism. There are two variants of CHC22 present in the human population and it has been proposed that the likelihood of an individual developing T2D is impacted by the type of CHC22 which they have. To investigate this further, I will work with purified CHC22 variants to compare their ability to assemble into protein baskets. We also seek to understand how CHC22 cages are subsequently disassembled, as this is currently unknown. This research will further our understanding of how glucose metabolism is regulated and provide insight into the pathology and potentially the treatment of T2D.


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