NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular regulation of autophagy in health and disease
Funder: Medical Research Council

Abstract: A major focus of this research is to decipher the signals that initiate autophagy and determine how these signals trigger autophagosome formation. Autophagy is a conserved catabolic process for degrading unwanted, damaged or foreign components in eukaryotic cells. Autophagy is critical for various physiological processes such as embryonic development and establishment of self-tolerance in the immune system. Additionally, malfunction of autophagy is involved in multiple human diseases including cancer, Parkinsons and Crohns. Autophagy occurs when a small membrane cistern grows and surrounds a portion of the cytosol, eventually sealing itself to form a double-membrane vesicular structure termed an autophagosome. The outer membrane of the autophagosome then fuses with the endocytic system to deliver the internal membrane and its contents to the lysosome for degradation and recycling. Under conditions of stress, such as nutrient starvation or infection, autophagy is strongly induced, yet the signaling pathways that lead to this increase in autophagic flux are poorly understood. We recently identified a protein kinase complex that is essential for the early stages of autophagy. The complex consists of at least three proteins: the kinase ULK1 and its accessory proteins ATG13 and FIP200. Importantly, it appears that this complex acts as a signaling node to convert incoming autophagy signals into autophagosomes. We aim to identify the signaling pathways that initiate autophagy with stimuli including nutrient starvation, ER stress and innate immune responses. Using biochemical and cell biological techniques we will define how these pathways interact with the ULK1 complex and in-turn how ULK1 kinase activity is altered. Importantly, we will use this information to determine the downstream targets of ULK1 to understand how autophagy is induced. Another related focus of the lab is to determine how autophagy can target specific cellular components in the background of all others. Traditionally autophagy was seen as a non-specific pathway, with random portions of the cytosol targeted for degradation. However, recent work has shown that autophagy can target specific proteins and organelles within the cell. For example, specific targets include mitochondria, which has implications for the neurodegenerative Parkinson's disease, and intracellular pathogens such as Mycobacterium tuberculosis. As with proteasomal-mediated degradation, ubiquitylation appears to be the signal for autophagic turnover. We are interested in how this ubiquitylation signals to the autophagic machinery, specifically the ULK1 complex, to trigger the switch from a general, non-specific autophagy into a targeted, specific autophagy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Ubiquitylation Signalling Mechanisms
Funder: Medical Research Council

Abstract: Ubiquitylation is a posttranslational modification that plays a role in almost every cellular process. Ubiquitin, a 76 amino acid protein can be covalently attached to substrate proteins. Residues within ubiquitin can themselves be sites of ubiquitin conjugation to result in the formation of ubiquitin chains. As a result, polyubiquitin chains of eight different linkage types having different topologies can be assembled. We now appreciate that ubiquitin chains of different linkage types adopt distinct conformations and have different functions. In order to achieve linkage-specific polyubiquitin recognition, binding proteins exploit these structural differences. However, many of these linkage-specific binding proteins or readers of the modification remain to be discovered. Research on uncovering roles for polyubiquitylation has been hampered largely by a limitation in the availability of tools to probe the ubiquitin system. Further, enzymes that regulate ubiquitylation and substrates that get ubiquitylated during immune signalling are not understood. We are particularly interested in uncovering ubiquitin-dependent signalling nodes in lymphocytes where the roles for ubiquitylation in adaptive immune responses are poorly characterized. Using immune cells as a model system we want to understand how cells use 8 different polyubiquitin types and what unique information is encoded by each of them. Deubiquitylases (DUBs) reverse ubiquitylation and are key regulators of the ubiquitin system. We study DUBs in the immune system and how DUB activity is modulated. Dysfunction of the ubiquitin machinery is a contributing factor to disease and a better understanding of the ubiquitin system will enable us to manipulate it and exploit components as targets for drug discovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Chemical Biology Approaches for Studying the Ubiquitin System
Funder: Medical Research Council

Abstract: Cellular proteins are subjected to a myriad of post-translational modifications which can alter protein fate and function. These post-translational modifications increase the functional repertoire of the surprisingly small number of protein-coding genes in the human genome. Protein ubiquitination is a post-translational modification which regulates most if not all aspects of eukaryotic biology. Defects in the process lead to numerous diseases such as neurodegenerative and inflammatory disorders. The research in my lab is focused on the ubiquitin conjugation machinery and the proteins responsible for decoding the numerous polyubiquitin signals. The ubiquitin conjugation machinery consists of hundreds of proteins which all function together in a coordinated manner. The mechanistic aspects of this machinery and the physiologically significant interacting partners are poorly understood. Furthermore, the ubiquitin conjugation machinery is not restricted to installing a single ubiquitin signal. Numerous polyubiquitin topologies can be assembled which can lead to distinct cellular outcomes. The effector proteins that engage many of these polyubiquitin topologies are unknown and their discovery would provide great insight into the cellular roles of these modifications. I use chemical biology and multi-disciplinary methods to develop and apply novel tools, which are tailored to address these important outstanding biological questions related to the ubiquitin system. This will ultimately reveal novel therapeutic targets and improve our understanding of disease pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Neighbourhoods and Communities
Funder: Medical Research Council

Abstract: Aims and objectives Interest in neighbourhood-level influences on health has burgeoned with research showing that although ‘who you are’ explains much geographical variation in health outcomes, there is also an effect of ‘where you are’. Neighbourhoods are also an important site for health improvement efforts, and population health monitoring. Although policy makers recognise that people’s health, wellbeing and resilience is affected by the quality of their environments, including the availability of green and open spaces, transport, housing, access to good quality food and social isolation, finding levers to bring about health improvement by changing neighbourhoods remains a significant research challenge. The aim of this programme is to further our understanding of the ways in which aspects of the local social and physical environment interact to influence health and the ability to lead a healthy life. Research plan and methodology The programme addresses two main research themes: 1. Living in deprived neighbourhoods is associated with poor health and life chances and there is an expectation that improvement to housing and neighbourhood conditions will improve health, however the evidence base to date is weak. Through face-to-face surveys and drawing on a range of existing data on levels of amenities and facilities in local neighbourhoods, we will investigate how area regeneration and housing investment affect individual and household health and wellbeing and explore the processes that support cohesive, sustainable communities. Although focused on regeneration in Glasgow, the aim is to produce findings that are transferable to other regeneration settings. 2. There is growing interest, and increasing policy attention, in the role of the neighbourhood context in determining the health and life chances of children and adolescents. Most studies to date have been conducted outside the UK, limiting their usefulness for policy development here. We propose to explore neighbourhood and community influences on a range of children and young people’s health and behaviours, with a particular focus on gathering objective measurements of physical activity (using accelerometry) and their location (using Global Positioning Systems) as well as developmental and behavioural outcomes. Moreover, although much attention is given to urban neighbourhoods, there have been calls to develop a better understanding of the differences between urban and rural life today and their importance to health, particularly among children and young people and identify the potential policy levers which could be tailored for different groups and contexts. Through our work on these two themes we will apply the knowledge gained to develop and evaluate interventions in collaboration with policy, practice and community stakeholders.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Informing Healthy Public Policy
Funder: Medical Research Council

Abstract: Aims and objectives We seek to understand how new policies and interventions are publicly debated and influenced; how research evidence is best synthesised and presented for use in the policy making process; and what approaches work best for generating high quality, relevant, timely evidence. Our aims are to better understand and influence emerging social and public health debates, to improve the way research evidence is reported, synthesised and then used in the policy-making process, and to apply robust approaches to evaluating policy interventions. We address these questions through three overlapping workstreams focused on: understanding emerging health debates; understanding policy and using evidence; and evaluating health and social policies. Our aim in the next five years is to combine high quality, translational public health science with an in-depth understanding of the political context of the policy process. In the longer term, our vision is to become a leader in the field of improving the timely translation of scientific knowledge into policies and interventions to improve population health and reduce inequalities. Research plan and methodology We have identified a series of guiding questions to address our objectives. To study how health issues, risks and evidence are understood and presented in major emerging public health and policy debates, we will ask questions such as ‘How can we better examine emerging public health debates by combining research on actors, processes and contexts?’ To improve the reporting, synthesis and translation of public health evidence into policy and practice, we will ask questions such as ‘How can we best combine high quality, translational public health science with an in-depth understanding of the democratic and political nature of policy-making?’ and ‘How can we improve the synthesis of the complex, heterogeneous evidence typical of population health intervention research?’ To identify, develop and apply robust approaches to evaluating major policy interventions and strategies, we will ask questions such as ‘What methods work best in the evaluation of complex policy interventions’ and ‘Are there novel approaches to evaluation in disciplines such as political science and economics that can be applied to public health evaluations?


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating chromatin and DNA structure to understand transcriptional regulation and genome stability
Funder: Medical Research Council

Abstract: This aim of this programme is to investigate chromatin structure and DNA topology to understand the fundamental mechanisms important for regulating gene transcription and genome stability. In mammalian cells all nuclear processes such as transcription, DNA replication and repair occur on a chromatin template so it is critical to understand its structure. Despite many years of research the structure of chromatin is highly contentious. We are using high-resolution microscopy techniques to understand chromatin fibre structure. This information will give insight into the fundamental building blocks that are critical for protecting the genome. To further investigate chromatin/DNA structure and function we are developing novel molecules in collaboration with the chemistry department that can be used as structure probes. These studies will enable us understand the relationship between chromatin structure and the regulation of transcription and genome stability. As an experimental model we are using cell lines and tissues from healthy individuals and patients with human genetic diseases. This experimental approach will enable us to better understand how the cell works normally and how it goes wrong during disease. To study genome stability we are using common-fragile sites as a model. These are regions of the genome that are present in all individuals but have a propensity to break under replication stress. By using a defined experimental system, like fragile sites, will enable us to better understand how the genome maintains its structural integrity and protects the DNA from damage. A number of human genetic diseases are directly linked to mutations in chromatin proteins and in diseases like cancer many genes are aberrantly expressed, caused by a loss of genome integrity. Understanding how DNA is packaged in human cells will give new insights into the mechanism of human disease and will lead to the development of new biomarkers and treatments The new molecules being developed in this project have two main purposes (i) as tools to investigate chromatin/DNA structure and (ii) as reagents that can be used to treat patients with diseases such are cancer. As these reagents have IP-potential we are investigating future commercial possibilities. Developmental of these reagents will promote interactions with industry and biotech companies leading to future better treatments.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular Genetics of Mammalian Cilia in Development and Disease
Funder: Medical Research Council

Abstract: Cilia are small, microtubule-based projections from the surface of most mammalian cells. Cilia regulate the responsiveness of the cell to key developmental signals, including Hedgehog (Hh) and Wnts. Cilia are distinct sub-compartments of the cell with unique membrane and cytosolic compositions, enriched in many receptors and signalling components. While recent studies have shown that mutations in genes required for cilia structure in both mice and humans result in a broad spectrum of developmental disorders, termed ciliopathies, little is known about how this compartmentalization of the cilia itself is maintained. The aim of our work is to investigate the genetic and molecular mechanisms regulating mammalian cilia compartmentalization necessary for development and tissue homeostasis. Using a combination of mouse models and primary cell culture, we hope to identify novel mechanisms of regulating traffic into the ciliary compartment. These studies will lead to a better understanding for the diagnosis and clinical management within ciliopathy spectrum. The objectives for this project are: 1) To investigate sorting mechanisms regulating traffic into the ciliary compartment. 2) To determine cell-specific physiological consequences of loss of ciliary trafficking. 3) To identify post-translational modifications which ”tag” cargo for dynamic and specific trafficking into and out of the cilia. Our overall aim is to generate new mouse models of human disease candidates, to correlate genotype, cellular phenotype, and overall health. We examine the effects of these mutations integrating microscopy, transcriptomics and proteomics. Taken together, we hope this work will help us evaluate how a genetic mutation leads to specific cellular and physiological consequences that will help to develop evidence-based strategies for clinical management of ciliopathies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Enhancing the MRC National Survey of Health and Development as an interdisciplinary life course study of ageing
Funder: Medical Research Council

Abstract: The MRC National Survey of Health and Development (NSHD) is the oldest of the British birth cohorts, and is unique in having data from birth to age 66 years on the health and social circumstances of a representative sample (N=5,362) of those born in England, Wales and Scotland in March 1946 (www.nshd.mrc.ac.uk). Enhancing NSHD is the core programme of the MRC Unit for Lifelong Health and Ageing, and combines a research and a resource function. The resource function is to curate, enrich and share the NSHD resource, on which all Unit programmes and research collaborations depend. In the last five years, we have completed the 23rd follow-up, a pioneering clinic data collection, with a high response rate, developed data sharing policies and web-based data sharing tools, raised the international and national profile of the study through the NSHD 65th birthday events, and enhanced NSHD through new biomarker and genetic data. A critical mass of biomedical and social scientists undertakes collaborative projects; since 2007, NSHD data has been shared with 211 scientists from 49 research institutions. The research function is to foster integrative research across the Unit programmes and with external collaborators, and to build capacity in life course epidemiology and ageing research. Ongoing studies include: the lifetime determinants of kidney function, thyroid function, and healthy ageing; the long-term health effects of exposure to air pollution; dietary studies; and genetic studies. Much of this work involves comparative research across cohorts. For example, LHA leads the Healthy Ageing across the Life Course (HALCyon) research programme which brings an interdisciplinary group of researchers to study life course determinants of three aspects of healthy ageing across nine UK cohort studies: physical and cognitive capability, social and psychological wellbeing and underlying biology, including aspects of physiology and genetics. More details can be found on www.halcyon.ac.uk. The two main research themes for NSHD in the next five years are: (1) healthy ageing and the management of health and health care needs as the cohort grows older, and how these are influenced by earlier life experiences; and (2) the biology of ageing, linking epidemiology and mechanistic science in this cohort study. The latter includes planned metabolomic and epigenomic projects, and a new research collaboration on the ageing lung. We also plan to extend HALCyon cross cohort research activities, data harmonisation and data sharing through our role in the new ESRC/MRC Cohort Resource Facility and through international collaborations.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Wellbeing and participation in older age
Funder: Medical Research Council

Abstract: Healthy ageing requires good objective function physically, cognitively, and socially and having a positive state of mind. This programme aims to determine what factors from childhood, adolescence and throughout adulthood, promote positive psychological wellbeing and social integration in older age. Since 2010, UK Government has been committed to monitoring and understanding national wellbeing and this new programme brings a life course perspective to help improve our knowledge of how social, economic and health domains across life may act together to influence psychological wellbeing in later life. Supportive social relationships are closely related to psychological wellbeing and to morbidity and mortality and identifying ways to support the capability to remain socially integrated is also a priority. The key aims of this new programme are to: describe social and psychological wellbeing among older people and how this is shaped by the childhood and adult social context and experiences; assess the bi-directional links between wellbeing and biological ageing and identify what distinguishes people who maintain high wellbeing despite health or other challenges. The programme addresses two themes and uses data from the National Survey for Health and Development (NSHD) and other longitudinal surveys. Under the lifetime social integration and ageing theme, we will develop longitudinal profiles of social integration and describe their relationship to childhood social and economic factors, and older age physical and cognitive capability and ageing biomarkers. Work, including voluntary work and caring, is a key component of integration into society and one focus of this theme. In an interdisciplinary, international collaboration, we will examine factors that promote the possibility to extend working life using cohorts from Britain and other European countries. An emerging literature supports the hypothesis that greater psychological wellbeing is protective for cardiovascular disease, cognition and premature mortality, among other outcomes. Under the psychological wellbeing and ageing theme, we will contribute to this field and assess dynamic associations between wellbeing and indicators of physical, cognitive and cardiovascular ageing. We are also planning to include intensive measurements in daily life at future follow-up of the NSHD to assess factors from across life that may contribute to understanding the links between daily stressors and day to day variations in wellbeing.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE
Title: Analysis of trials, meta-analyses and observational studies
Funder: Medical Research Council

Abstract: Appropriate analysis of trials is vital to obtain a full return on the investment made through efficient design and excellent conduct. However, this is often far from straightforward. We are focusing on those which arise directly from our clinical studies. Thus we are investigating how to analyse multi-arm multi-stage (MAMS) trials, and how best to analyses time-to-event outcomes and recurrent events within trials, as well as using causal models to answer questions not addressed by randomisation. We are also examining the analysis, validation and handling of missing data in multivariable prognostic models; and one versus two-stage and network meta-analysis approaches using individual participant data. Clustered data often arise in trials and observational studies so another focus is the Appropriate analysis of longitudinal and clustered data.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE