NIHRDataInsights/HRCSData huggingface dataset:
Title: Quantitative Systems Biology
Funder: Medical Research Council

Abstract: Many cell types respond to extracellular signals with an increase in intracellular Ca2+ and activation of the phosphatase Calcineurin (Cn). In vertebrates, Cn de-phosphorylates the cytoplasmic components of NFAT transcription complexes (NFATC1-C4, Nuclear Factor of Activated T-cells, Cytoplasmic component 1-4), resulting in their nuclear entry. In the nucleus, NFAT proteins and several co-factors assemble on DNA and activate transcription. Nuclear entry is counterbalanced by kinases such as DYRK1A and GSK3b, which phosphorylate NFAT molecules promoting their nuclear export. In addition, RCAN1 (encoded by the DSCR1 gene) is a molecule that inhibits Cn function thereby acting as a negative regulator of NFAT.||One of the remarkable features of NFAT signalling is its positive and negative feedback control. In fact, NFATC1 and C4 are known to activate their own promoters, therefore establishing a positive feedback loop, while expression of RCAN1 is also controlled by NFAT, yielding a negative feedback loop (See cover figure for details). This pathway is also the target of the immunosuppressive drugs Cyclosporin A (CsA) and FK506, which inhibit Cn within minutes, allowing both effective treatment of organ transplant patients at nM concentrations as well as rapid and precise loss-of-function experiments.|Cn/NFAT signalling regulates many aspects of vertebrate development and organogenesis, and failure of proper signalling has been associated with a variety of human diseases. These include defects in the immune system, propensity to AIDS, failure of proper patterning of the vascular and nervous system, heart valve malformations and mental retardation. More recently, the NFAT network has been considered as a possible site of perturbation to cure osteoporosis and juvenile diabetes. In addition, instabilities in this pathway have been shown to promote aberrant cell proliferation in breast and prostate cancer, and leukaemia. One of NFATs major targets is the angiogenesis factor VEGF, among the most promising targets for cancer drugs for solid tumors.||We are interested in measuring and quantifying all the necessary kinetic parameters and the absolute mRNA and protein concentrations of the constituents of the Calcineurin/NFAT signalling pathway in a variety of tissues. In addition, we will use mathematical modelling to simulate and accurately predict the associated spatio-temporal dynamics and to discover new pathway modulators. By means of computational predictions and experimental verification of the complex combinatorial logic, tissue specificity and DNA binding properties of the NFAT transcription complexes, we seek to extend the circuit above and to simulate its in vivo dynamic properties.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Epithelial morphogenesis and cell polarity
Funder: Medical Research Council

Abstract: The regulation of Epithelial cell polarity specification and maintenance is a key problem in cell biology. The vast majority of cancers in human originate from epithelia (i.e. Breast, Colon, Lung, Kidney etc.) and a major hallmark of tumourogenesis is a progressive loss of epithelial cell polarity. This eventually leads to Epithelial to Mesenchymal (EMT) cell transition a key step toward cell metastasis activity. Epithelial cell specification presents the converse step (i.e. Mesenchymal to Epithelial transition, MET). Better understanding the molecular mechanisms and signalling pathways required for promoting MET is therefore a key step toward a better understanding of EMT.||To tackle this question in vivo, we are using the genetically amenable Drosophila melanogaster. While up to 80% of the genes associated with diseases in human, are conserved in Drosophila, they are often present as one single locus, which is ideal as very little redundancy is present. So far this approach has allowed us to characterize the function of the conserved tumour suppressor PTEN, during epithelial apical membrane morphogenesis. PTEN is mutated in more than 50% of cancers in human. In epithelial cells, PTEN is recruited at the developing zonula adherens (za) through direct binding to the conserved polarity gene Par3/Baz. Our work in Drosophila has now been confirmed and validated in mammalian epithelial cells, by two other independent groups. Since then, we have tried to better characterize the PTEN/Par3 interface and in particular we have focussed our work on the problem of za morphogenesis and maintenance. The za is the principal membrane domain for the cells to form an epithelial sheet, as this domain is responsible for cell-cell anchorage. We believe that we have now solved a number of key open questions in this field of research. In particular, we have recently solved the molecular basis for Par3 requirement during za assembly in epithelial cells. Par3 and PTEN are also key genes for directed cell migration and we propose that in pathological conditions such as cancer, defect in their regulation in epithelial cells (i.e. phosphorylations/localization), and are likely to have a profound impact toward cell metastasis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The functions of MAPK signalling pathways in cell regulation and disease
Funder: Medical Research Council

Abstract: Mitogen activated protein kinase (MAPK) cascades are important mediators of a cells response to external signals such as mitogens and cellular stress, and are implicated in many cellular process including cell survival, proliferation, differentiation and migration. Deregulation of MAPKs is implicated in several diseases including inflammation, cancer, neurodegeneration and addiction, and drugs that target these kinases may represent a powerful way of treating these diseases. Despite this, the downstream mechanisms by which MAPKs produce the appropriate responses in cells are not well understood. We are interested in how activation of the MAPKs p38 MAPK and the MAPK-activated kinases MSK1 and MSK2, controls physiological or pathological functions in cells. While MAPK signalling is important for the correct function of many cell types and tissues, several of these kinases, including MSK1 and 2 are highly expressed in immune and neuronal cells. One reason for this may be that both cell types respond rapidly and continuously to extra-cellular signals. We are investigating the roles that MSK and p38 MAPKs play in neuronal and immune model systems using a combination of gene targeted mice, specific cell permeable inhibitors, microarrays, QPCR and proteomic techniques. We are especially interested in how MAPK signalling controls transcriptional reprogramming in neurons and immune cells, both by targeting specific transcription factors, such as CREB and ATF1, and by modifying chromatin proteins such as histone H3. We are also interested in the roles that MAPKs play in the negative regulation in the innate immune system. Finally we are also interested in the intriguing possibility that MAPK signalling may regulate the production of specific microRNAs in cells. In collaboration with others we are also looking at the effect of the gene targeting of MAPKs in models of arthritis and inflammatory bowel disease, inflammatory pain, addiction and circadian rhythms Together, these studies should increase our understanding the physiological and pathological roles MAPK signalling in the CNS and immune systems, and identify potential targets for therapeutic intervention in these systems


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Ethnicity and health
Funder: Medical Research Council

Abstract: Addressing ethnic inequalities is a key aspect of initiatives of UK governments and also of international organisations. In spite of considerable research, the causes of ethnic differences in health (e.g. excess hypertension in Black African origin and coronary events in South Asians) remain a scientific and policy challenge. The overall aim of our programme is to focus on how the timing and duration of social exposures are related to ethnic differences in health and health related behaviours over the life course. This allows us to identify key time points when interventions to reduce ethnic inequalities in health could be most effective, but also gives insights into improving health outcomes for all groups, especially where some ethnic groups do better than average. Our objectives are to investigate: (1) the extent to which social, economic and psychological circumstances contribute to differences in health at different stages of the life course within and between ethnic groups; (2) change and stability in key influences on health such as family life, socio-economic disadvantage and neighbourhood environments and (3) the extent to which and why the health of ethnic groups of similar ancestry varies in different country settings. The lack of longitudinal studies of ethnic minorities has made it difficult to investigate when health differences emerge, and to understand transmission of health potential across generations. Our Determinants in young Adulthood Social well-being and Health (DASH) study is a unique resource that we use to track ethnic differences in cardiovascular, respiratory and mental health from youth to adulthood. DASH started in 2002/03 with about 6000 11-12y olds, 80% ethnic minorities, in 52 schools in London. The cohort is now aged 21-23y and a feasibility study is currently examining the possibility of follow-up in different locations (e.g. GP surgeries, clinical research facilities, homes, community pharmacies), collecting bio-marker data for the first time, and establishing culturally appropriate psychosocial measures for this age group. Our international comparative studies include countries at different stages of development, examining how migrant groups fare in different settings. The findings from our observation studies have led to the development of complex intervention studies, including the prevention of obesity in ethnic minority young people, improving the quality of life of breast cancer survivors, reducing work related injuries inn migrant workers. Various activities in the communities foster information exchange and ensure culturally appropriate designs.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Gender and Health
Funder: Medical Research Council

Abstract: It is often assumed that gender differences in health are inevitable and constant. However, current research is beginning to take a far more critical view of the links between gender and health. We are undertaking studies explicitly examining the patterning of various health indicators by gender, and the relationship between gendered constructions of identity and health and health behaviour, using a range of methods, with the aim of developing or contributing towards interventions which improve the health of men and women. This programme aims: to examine gender differences in various dimensions of health, taking into account different historical and cultural contexts; to examine acquired risks of ill health, particularly key health behaviours (smoking, alcohol consumption and obesity), and how these are distributed among and between men and women, and how they influence and are influenced by social constructions of gender (masculinities and femininities, and gender-related roles and attitudes). to examine the factors mediating men's and women's recognition, reporting, and experience of ill health, and help seeking behaviour; patterns of consultation in men and women with similar morbidity; gender and decisions to consult (or not); and to develop gender-sensitised interventions (where appropriate) to improve the health of men and women. A range of studies or reviews using different social scientific methods is involved, including: Primary and secondary analysis of quantitative data from studies in Social & Public Health Sciences Unit and national surveys (e.g. Twenty-07, Health Survey for Scotland, British Household Panel Survey) and routinely collected data (e.g. THIN) and international data. Gender and the experience of health and illness (qualitative studies, including primary data collection and analysis, and secondary analysis of existing qualitative data) Changing gender differences in health in childhood and adolescence. Illness experience among chronically ill men and women Men and women's views of masculinity and femininity, male/female identity and health Patterns of consultation and decisions to consult in men and women with similar symptoms or illnesses. Lay understandings of health. Patterns of health behaviours by gender, and whether these may vary geographically or by other social statuses. Gender role orientation and attitudes and alcohol consumption and smoking; ways in which health behaviours may be signifiers of gender. Exposure to health behaviours (smoking, alcohol consumption and illicit drug use) in films and health behaviours in adolescence in Scotland, and in comparison with other European countries. Media presentations of men and women and health and illness Randomised control trial of behavioural interventions to reduce obesity


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE
Title: Evaluating the Health Effects of Social Interventions
Funder: Medical Research Council

Abstract: This programme, funded by the Chief Scientist Office (CSO) of the Scottish Executive Health Department, aims to produce evidence to support public health decision-making by evaluating the health impacts of social interventions. Our research involves evaluations of the health effects of housing, regeneration, transport, employment, tobacco control and other policies, and their effects on health inequalities. To do this we undertake new controlled studies, mainly using quasi-experimental methods; qualitative research, and systematic reviews. The main objectives of the programme are to: • Undertake systematic reviews of the effectiveness of social or health interventions (policies, programmes and projects) in improving health, and • Carry out primary studies evaluating the health impacts of social and health policies and interventions. The focus of our current research is examining the effects on health and health inequalities of housing and regeneration, employment and welfare, and school contexts, inequalities and health. We also participate in projects aimed at developing new methodologies for evaluation and evidence synthesis.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining Signatures of Function and Selection within the Human Genome Sequence
Funder: Medical Research Council

Abstract: This work is narrowing the divide between a rapidly-increasing volume of genomic data and a less-rapidly expanding breadth of understanding of biological function. Its principal goal is to determine molecular mechanisms that contribute to human disease. Overview Sequencing the human genome was an enormous technological feat. The challenge for forthcoming years is to understand the molecular bases of human biology and disease using the insights that evolutionary analyses of this sequence afford. Only then will technological and conceptual advances be translated efficiently towards the clinic. Costs of genome sequencing and resequencing are plummeting, with costs halving every 12-20 months. Clearly, the steady trickle of genome sequences is becoming a torrent. The genomes of tens of thousands of patients, all model organisms, most mammals and primates, human parasites and pathogens will soon be available. Data management, analysis and interpretation are presenting huge logistical challenges. Nevertheless, these data have the exciting potential to link genotype variation at single base, kb and Mb scales to phenotypic differences that are relevant to the prevention, diagnosis and treatment of human disease. Aims Our research is placed at the intersection between disease genomics, computational biology and molecular mechanism determination. We are exploiting RNA and DNA sequence data to illuminate the molecular pathoetiology of human disease. We are beginning to develop transcriptional atlases for cells and tissues in order to better understand their functional repertoires. Our primary aim is, however, to exploit all genome-scale data sets to identify or prioritise genes that are mutated in human disease. For example, we have a large programme of work investigating the genetic variants that underlie the onset of Parkinson’s disease. Our computational-experimental RNA research (co-funded under an ERC Advanced Grant, with the Liu group) is identifying noncoding RNAs that explain the molecular mechanisms of Mendelian and complex neurological disorders. The group is also working with colleagues at the Sanger Institute to develop approaches to sequence DNA or RNA from single cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Small RNA Regulation in drosophila
Funder: Medical Research Council

Abstract: Intracellular compartments such as organelles are essential for a cell’s function. RNA occurs in every compartment in a cell. Research in the Liu group focuses on three fundamental questions relating to RNA, for which we seek an in vivo understanding. We choose the fruitfly drosophila melanogaster as our prime model system because of its genetic tractability and the depth of genomic data. Studies in drosophila have provided a key to vertebrate development and human biology. First, we will study the mechanisms by which the synthesis of CTP, one of the critical precursors of RNA and DNA, is compartmentalized within a cell. We have recently discovered that CTP synthase is compartmentalized in a novel evolutionarily conserved organelle, the cytoophidium. Compartmentation is essential for the localization of biological processes within a eukaryotic cell. CTP synthase has been an attractive target for developing agents against cancer, virus and parasites. We will investigate how CTP synthase is assembled into the cytoophidium and how the cytoophidium is linked to cancer biology. Second, we are interested in the biological roles of long noncoding RNAs in drosophila. While much knowledge has been gained on the functionality of protein-coding genes, we know very little about the mechanisms by which noncoding RNAs function in a fly. We will analyse the spatial and temporal expression of long noncoding RNAs during drosophila development and will investigate the underlying mechanisms of how they function in vivo. Finally, we will investigate how an RNP assembly and RNA splicing factor SMN and the abundance of U bodies are regulated during development. SMN, a major constituent of U bodies which contain snRNPs, is the determining factor for SMA. The study of SMN and the U body thus holds the key to identifying the cellular mechanism of SMA. We are particularly excited to investigate the role of SMN in the maintenance of stem cells and their pluripotency.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Chemistry of Bicycles
Funder: Medical Research Council

Abstract: Peptide libraries are a rich source of molecular diversity and potentially of powerful drugs. However, peptide drugs suffer from a number of systemic shortcomings inherent in peptide structure and chemistry. These include poor affinity for target due to conformational flexibility, poor serum stability and low bioavailability. Macrocycles are a class of powerful natural drugs and toxins derived from peptide backbones. Their structures reveal strategies (such as cyclization, chemical modification and cross-linking) that address the shortcomings of peptide drugs. However, in nature, macrocycles are produced through dedicated non-ribosomal synthesis pathways, which, so far, have proved refractory to engineering or evolution to produce tailor-made compounds. This research program is aimed at the synthesis and evolution of peptide macrocycles with therapeutic potential using ribosomal peptide synthesis and harnessing both natural and chemical combinatorial diversity for directed evolution of novel peptide macrocycles. In particular, the program is aimed at the phage display of diverse peptide libraries comprising a defined number of chemical functionalities that allow peptide cyclization and folding around one or multiple organic cores. By tethering discrete peptide loops to a chemical and rigid scaffold this strategy not only constrains conformational flexibility, and greatly reduces susceptibility to proteolytic degradation, but also extends the chemical diversity of peptides by virtue of the organic core, which may include a wide variety of functionalities not present in nature. Chemical diversity may be further expanded through the incorporation of unnatural amino acids in the peptide loops, specific chemical modification of side-chains and / or N- or C-termini. In combination with the power of repertoire selection, this approach promises to deliver tailor-made designer ligands of low molecular weight, defined compact structure and high serum stability with obvious potential as a novel class of bio-therapeutics.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE