NIHRDataInsights/HRCSData huggingface dataset:
Title: Life course methods and functional trajectories
Funder: Medical Research Council

Abstract: Aim This underpinning theme provides the statistical resource to support all programmes in their analysis of complex longitudinal data Importance Knowledge of life course trajectories of subclinical health-related traits are vital to the understanding of the development of disease and morbidity in later life. Repeated measurements of body structure and function, and of environmental exposures and lifestyle, are collected in longitudinal cohorts such as the MRC National Survey of Health and Development (NSHD), providing unique opportunities to study effects of exposure across the whole of life. Lifetime patterns of exposure can thus be assessed, and such patterns may be a stronger predictor of later life health and ageing than a single midlife measure. Further, such data allows for the testing of sensitive periods during the life course during which exposure may have the greatest effect on an outcome, or for assessing whether accumulation of exposure is most relevant. Thus it is possible to identify when in the life course intervention may be most effective. Methods Understanding what constitutes a healthy trajectory into old age, and how midlife change is related to later life trajectories are important in order to appropriately manage risk factors in older people. The modelling of trajectories as a repeated outcome measure are standard, but more novel approaches are required to deal with, for example, inter-relationships between different functions. Further, research has focussed on associations with the smooth average long-term changes, with less attention paid to shorter-term fluctuations, variability or the immediate impact of health or social events. We will apply standard and novel statistical methods to these problems Translational implications These techniques, applied to specific scientific questions in each of the programmes, has the potential to identify critical or sensitive periods during life which determine disease risk, and where intervention could potentially be the most effective


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Complexity in Health
Funder: Medical Research Council

Abstract: The complexity in health programme aims to improve the design and conduct of population health improvement research, through development and translation of methods and their implementation in studies. An increasing focus will be to prioritise complex adaptive systems approaches to intervention and evaluation: “Instead of asking whether an intervention works to fix a problem, researchers should aim to identify if and how it contributes to reshaping a system in favourable ways.” A major ambition is to develop methods and approaches which facilitate partnership at all stages of complex intervention research between interdisciplinary researchers and key stakeholders in real-world settings – policymakers, practitioners, and the public. The aims of our planned programme of work focus on key areas where progress is required: (i) to develop better methods to co-produce intervention programme theory and use this to identify key uncertainties, guide the choice of evaluation perspective and the prioritisation of research questions and identify the appropriate research design; (ii) to develop and translate methods and processes that support the involvement of stakeholders in all stages of development, evaluation and implementation; (iii) to develop and normalise a wider range of approaches to evaluation, including complex systems approaches and other methods more suited to the evaluation of meso-, macro- and multi-level interventions; (iv) to improve the efficiency of research and its relevance and translation into policy and practice. To achieve these aims, we will organise our work in four workstreams. The methods workstream will develop and translate methods to improve the design, conduct and utility to decision-makers of public health improvement research, with a significant focus on co-production of programme theory to inform intervention and evaluation design. It will include methods development to improve the application of agent-based models (ABMs) in population health. The modelling workstream will apply ABMs to a range of public health issues including social care, welfare reform and place-based health. The interventions workstream will work with colleagues and multi-sectoral collaborators to identify and/or develop novel interventions and evaluate them and their implementation in real world settings, particularly focussing on adolescent health and healthy ageing. The educational settings workstream will focus on school based interventions with an emphasis on adolescent mental health.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Inequalities in health
Funder: Medical Research Council

Abstract: The aim of this programme is to improve understanding of inequalities in health. We produce important methodological development and emphasise improving understanding of the causes of inequality to inform policy or other intervention strategies, largely using observational data. Our objectives are: 1. To improve population health and reduce inequalities through research that advances understanding of the determinants of health and health inequalities. 2. To inform and evaluate policy and large-scale interventions that will reduce health inequalities through the conduct and translation of research. 3. To exploit and enhance routine, linked and population-sampled data sources, maximising the return on the investment made in these resources and the underlying infrastructure. 4. To develop and build capacity in methods for measuring, understanding and reducing inequalities in health using observational data. We will continue to provide leadership in the methodological challenges underlying research into inequalities in health. The programme is presented in four workstreams. Workstream 1: “Measuring inequalities” capitalises on our expertise in linked data to assess the nature and extent of inequalities in health and behaviours. Workstream 2: “Understanding inequalities” develops and applies causal methods to determine the root causes of health inequalities. Workstream 3: “Reducing inequalities” examines how health inequalities may be reduced, particularly through the restructuring of social protection and other large-scale policies and interventions. Workstream 4: “Inequalities in the workplace” considers the relationships between work and health as a means of reducing inequalities in the working age population. Together, these workstreams provide a progression of health inequalities research: describing the problem, understanding the causes, and establishing what works to reduce inequalities in population and workplace settings in the UK and internationally.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Relationships and Health
Funder: Medical Research Council

Abstract: Positive social connections are protective of health. Social relationships can be strongly supportive, but can also be a source of poor health and risk behaviour. Our aim is to progress understanding of mechanisms linking relationships to health and translate this knowledge into relationship-based solutions to key population health issues. We have three primary objectives: - To uncover multilevel and modifiable relational mechanisms that shape, and are shaped by, experiences of wellbeing, health, risk, illness and inequality; 1. - To improve methods for discovery and translational public health research focused on relationships and health; 2. - To co-produce and evaluate relationship focused solutions to key public health priorities. The programme conceptualises relationships as inherently complex, heterogeneous and influenced by the social context in which they are enacted. Our research is framed by complex systems thinking, in which social relationships are construed as interdependent elements within a connected whole. Our emphasis is on transdisciplinary action research, involving partnership with stakeholders throughout the research cycle, from problem framing, through measuring and describing, to identification and evaluation of potential solutions. Our three complementary workstreams are structured around the levels at which social relationships operate; in dyads, small groups, social networks and communities. The first focuses on intimate relationships and families. We aim to lead internationally on the public health conceptualisation and measurement of sexual wellbeing, and on the co-production and evaluation of complex interventions that theorise and measure relational mechanisms of change. This includes sex education, whole-school approaches to gender-based violence, and prison-based parenting programmes. The second examines the distinct influences of social networks on health. We seek to advance methodological innovation in capturing and analysing multi-layer networks and using this to optimise network-based interventions. We will advance understanding of how evolving digital interactions have altered relational influences on adolescent health. We will also develop novel methods to assess change in social networks over the lifecourse, using causal mediation methods to assess relational elements of inequalities in healthy ageing. The third focuses on social relationships in communities. We will use a syndemics lens to advance understanding of health inequalities in marginalised communities; we will engage network analysis to establish the most effective ways of harnessing formal network support in areas of high deprivation; and we will employ systems thinking methods to understand the complex causes of social isolation, working with stakeholders to identify whole-community and strengths-based ways to tackle it.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Places and health
Funder: Medical Research Council

Abstract: We know that our living environment affects our health. One implication is that environment could be a lever to improve population health and narrow inequalities, but there is currently little robust evidence about what the best interventions or investments for health would be, how long they might take to work, and the likely extent of benefits. Building on our past work, the programme aims to tackle that lack of evidence and the reasons for it, in the next five years and beyond. A distinguishing feature of the Places programme is its focus on connections between environment, people and health. As social as well as epidemiological scientists, we conceptualise and research places as social, economic and environmental systems which shape and are shaped by individuals. In practice, this means we focus on time as well as space; a longitudinal perspective is needed to see how people and places affect each other. The programme’s long-term aim is to understand how urban environments do, or can be modified to, protect and improve population health and reduce health inequalities. The objectives are to i) lead a step-change in the availability and application of novel data and methods to improve understanding of how places affect health; and ii) utilise these new methods and data to identify and evaluate place-based interventions for improving population health and reducing health inequalities. We will deliver these aims via 3 interconnected workstreams. Workstream 1 creates and uses longitudinal data to tell us how places change over time and the consequences for population health and related behaviour. Workstream 2 collects and uses GPS data and approaches developed from ecology to tell us how people use places; how the content and configuration of settlements affects where they go, what they do, and what this means for their health. Workstream 3 creates dynamic simulation models to explore both how people, place and health are linked in systems, and how places can be changed to improve health and reduce inequalities. The health and health-related outcomes of primary interest are mental health and wellbeing, exposure to alcohol and tobacco environments, contact with nature, physical activity, and population-level indicators of health such as mortality rate.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: GENERIC HEALTH RELEVANCE
Title: Systems Science Research in Public Health (SysSci)
Funder: Medical Research Council

Abstract: In their Industrial Grand Challenges, the UK Government has set the twin targets of increasing healthy life expectancy by five years by 2035 whilst narrowing the gap between rich and poor. Healthy life expectancy, including inequalities in it, are considered in the Scottish National Performance Framework, the National Indicators for Wales and the Northern Ireland Outcomes Delivery Plan. The aim of this programme is to provide underpinning research that can support decisions around which combination of policies and interventions, over which timescales, and implemented with which intensity, are most suitable to bring about the whole-systems change required. It also seeks to understand how to lock in gains over the longer term. Our focus will be on identifying policy and intervention options with the capacity to multi-solve, that is to exploit the interdependencies and synergistic dynamics between multiple government priorities, such as health and wellbeing, economic prosperity, strong communities, housing, and climate resilience. The programme will carry out interdisciplinary, collaborative research and methods advancement to develop and apply soft systems approaches and simulation modelling. It will seek to build new capacity in soft systems methods and system dynamics, and draw on existing Unit/University strengths in data sciences/big data, health inequalities, microsimulation and agent based modelling. The objectives are: 1. To improve population health and reduce inequalities through novel systems science research on the interdependencies between the wider determinants of health, and the policies and interventions that affect them. 2. To work closely with policy makers to support adaptive policy design under conditions of uncertainty – informing the design, implementation and iterative refinement of public health-relevant policies and large-scale interventions. 3. To develop and build capacity in systems science methods applied to public health grand challenges. 4. To provide systems science input into research programmes across the Unit, the wider university and beyond. As a new programme added after the main QQ process, the focus in the first 12 months will be to - appoint researchers at junior and senior levels with relevant methodological skills - develop collaborations and networks across the university, and with key systems science research groups in the UK and internationally.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Mitochondrial complex I: An intricate energy-converting machine, a cornerstone of mitochondrial metabolism, and a locus of mitochondrial dysfunction and disease
Funder: Medical Research Council

Abstract: Mitochondrial complex I (NADH:ubiquinone oxidoreductase) powers ATP synthesis by oxidative phosphorylation, exploiting the energy from reduction of ubiquinone by NADH to drive protons across the energy-transducing inner membrane. Being also required to maintain the redox status of the mitochondrial NAD+ pool to keep the tricarboxylic acid cycle and β-oxidation running, it is a keystone of mitochondrial metabolism and crucial for the survival of human cells. Consequently, mutations in its subunits and assembly factors that impact on its structure, function or biogenesis cause mitochondrial diseases, it is a drug target in diabetes, ischaemia-reperfusion (IR) injury and cancer, and complex I-linked drug toxicity compromises drug discovery programmes. Understanding the function and dysfunction 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, mechanism and assembly is required to underpin biomedical studies of complex I in mitochondrial and cellular systems of greater complexity. The Mitochondrial Complex I group aims to develop and apply this basic knowledge to understand and address the role of complex I in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Mitochondrial transport proteins: Highly dynamic integral membrane proteins required for the translocation of metabolites and cofactors, key to the function of the mitochondrion
Funder: Medical Research Council

Abstract: The transport of ions and small molecules across the mitochondrial inner membrane is required for many metabolic pathways, such as oxidative phosphorylation, amino acid metabolism, and synthesis of iron sulphur clusters and haem, but also for ion homeostasis, macromolecular synthesis, heat production, mitochondrial dynamics, signalling, cellular differentiation, development, and cell death. We study these transport processes to obtain a better understanding of their involvement in human physiology and diseases, focussing on four major aims. Firstly, we will elucidate the structural mechanism of mitochondrial transporters to understand the molecular basis of human diseases. We will complete our structural analysis of the mitochondrial ADP/ATP carrier by determining the substrate binding mechanism. We will also prioritise the structures of transport proteins with established links to disease: the uncoupling protein, a potential drug target for obesity treatment; the mitochondrial Mg-ATP/phosphate carrier, a regulator of ATP output; the aspartate/glutamate carrier, the molecular cause of citrin deficiency; and the mitochondrial pyruvate carrier, a major drug target. Secondly, we will establish the molecular identities of transport proteins and channels to enhance our understanding of their role in cellular processes and human diseases. For this purpose, we have developed techniques, such as thermostability shift assays and transport robotics, but we will also develop new methods, such as the exchange of light and heavy labelled metabolites. Thirdly, we will collaborate with physicians and medical researchers to identify metabolic, neuromuscular and developmental diseases caused by impaired mitochondrial transport proteins. We will exploit genomic analysis to identify new links to disease and we will characterise the disease variants. Fourthly, we will continue and extend our translational projects towards therapies, focussing on citrin deficiency, mitochondrial toxicity, specific inhibitors of the mitochondrial pyruvate carrier, and drug screening activities for transporters that are central to metabolic disease and cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Mitochondrial Genetics: Mitochondrial genome engineering to unravel the genetic links between mitochondrial gene regulation and human disease for future mechanism-based therapies
Funder: Medical Research Council

Abstract: Mitochondrial diseases caused by mutations in mitochondrial DNA (mtDNA) or mutations in the nuclear genome (nDNA) impair energy metabolism and other aspects of cellular homeostasis. More than half of mitochondrial diseases stem from defects of mtDNA maintenance or expression. Our incomplete understanding of the underlying biology and scarcity of animal models of mtDNA disease hinders the development of curative treatments for these disorders. The aims of the Mitochondrial Genetics programme are to engineer the mammalian mitochondrial genome to develop unique in vitro and in vivo models of mtDNA dysfunction and to exploit these models to interrogate mitochondrial genome regulation and to improve pre-clinical evaluation of treatments. These future aims build upon considerable successes of the past quinquennium and leverage the emerging technical developments in direct DNA base editing. One way of achieving these objectives will be to generate an in vivo mouse model of single large-scale mtDNA deletions (SLSMDs) and use it, together with other existing mouse models, to refine pre-clinical gene therapy approaches aiming at elimination of heteroplasmic mutant mtDNA by programmable nucleases, and to investigate mtDNA regulation. In parallel, we will employ emerging DNA base-editing technology to install de novo mtDNA point mutations in vivo, to create a base-editor library for systematic ablation of all mtDNA-encoded protein and tRNA-coding genes in mice, and to generate mouse models mimicking the most common pathogenic mtDNA mutations (e.g. m.3243A>G). We will also continue our work on the mechanisms of mitochondrial gene expression; albeit with increasing involvement of mouse genetics and mtDNA-editing methods, focussing on knowledge gaps in quality control and decoding during mitochondrial translation and mitoribosome assembly.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE