NIHRDataInsights/HRCSData huggingface dataset:
Title: Relationship between protein deficiency and sarcobesity in older urban black Cape Town populations: a feasibility study of diet interventions
Funder: Medical Research Council

Abstract: Low and middle income countries (LMIC) are burdened with increasing non-communicable disease (NCD) against a background of high communicable disease (CD) prevalence. South Africa is no exception with a pre-existing background of e.g. HIV/AIDS and tuberculosis and increasing cardiometabolic disease. CD and NCD interact to increase the rate of ageing. The force of this effect is felt most by older people in South Africa and other LMIC. One contributor to loss of independence in old age is sarcopenia, the loss of muscle strength and mass that occurs in ageing. NCD and sarcopenia are considered diseases of ageing. It is well known that adequate nutrition can moderate both sarcopenia and NCD as well as protect against infection. Public health advice on proper nutrition could therefore make a large difference to health in LMIC just as such it did in developed nations in the early 20th century. To develop and disseminate advice policy makers need data on current dietary habits. We already know that 18-64 year old black South Africans are protein deficient. Older black South Africans are also likely protein deficient but the diet patterns and macronutrient intake of this population are unexplored. In this project, we will gather preliminary data on the dietary patterns and nutritional intake of older black South Africans. We will examine whether older black South Africans are protein deficient and how this relates to the prevalence of sarcopenia and both CD and NCD in this population. Finally, we will assess how economic restraints on nutrition might compromise the usefulness of nutritional advice for older black South Africans. Our aim is to generate data that can be used by individuals, communities and policy makers to provide nutritional advice which has a positive effect on the health and quality of life of older people in LMIC.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Exploring Narrative Storytelling as Mental Health Support for Women Experiencing Gender-based Violence in High Prevalence Settings.
Funder: Medical Research Council

Abstract: Our partnership brings together medical experts, poets, civil society organisations, and feminist activists working on GBV in the UK and across the Middle East, North Africa and Asia to develop a narrative storytelling approach to gender-based violence (GBV) against women in high prevalence settings. Setting that have a high prevalence of GBV (where over 50% of women experience violence in their lifetime) are often countries or regions where GBV is publicly accepted as a normal part of women's everyday lives and condoned by state inaction. This is the case in the regions and countries included in our proposal, namely: Afghanistan, Kashmir (India), Tunisia, Kurdistan (Iraq), and Turkey. Storytelling is widely used as a means of personal expression in response to violence in these contexts, drawing on their shared socio-cultural origins as ancient Persian societies. Our collaboration draws on this shared history and the cultural importance of storytelling to develop a culturally-relevant intervention for women experiencing gender-based violence. We do this through four main activities: (1) collaboratively designing a potential storytelling intervention based on our team's diverse expertise from the medical sciences (psychiatry, psychology) and the humanities (humanitarian ethics, gender and women's studies, literature studies, poetry); (2) tailoring and piloting the intervention with women residing in safe houses in Kurdistan (Iraq); (3) developing an online networking tool to foster collaborations related to the pilot study and build future project ideas; and (4) creating a collection of stories based on women's accounts to reach a broad national and international audience to effect social change. This is an innovative approach to creating a culturally-relevant intervention to address the mental health needs of women experiencing GBV in high prevalence settings and will ideally challenge discourses that accept violence in the lives of women as part of a broader project of social change.


Research activity codes: 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: Women's empowerment and child health: exploring the impact of Rojiroti Microfinance in poor communities in Bihar, Northern India
Funder: Medical Research Council

Abstract: Every year, 2.2 million children die of malnutrition. Many more feel the effects of malnutrition on their health and intellect. Programmes to combat malnutrition include: distributing food directly; giving children micronutrients; giving nutritional advice; and protecting malnourished children through immunisation. Research by the World Health Organisation (WHO) has shown that these strategies can lead to better nourished children. However, these approaches may fail to reach those most in need (those living in extreme poverty). In very poor countries, where men are dominant, women are often prevented from making important family decisions and this may be linked to poor nutrition in their children. We are a group of community workers, economists, social scientists and doctors. Our partners are the Centre for Promoting Sustainable Livelihood (CPSL) - which is a non-governmental organisation in India; a UK charity (Rojiroti UK); the School of Sociology & Social Policy; and the School of Medicine (both at the University of Nottingham). Our team have experience of helping very poor people in rural areas of India to fight poverty. Our community workers encourage people in poor hamlets or ""tolas"" in Northern India to form self help groups (SHGs). Most SHGs are formed by women. They are asked to save a little money regularly, initially Rs2.5 (3 pence) per week. If they save regularly, their savings entitle them to a loan.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Integrating genome structure and function
Funder: Medical Research Council

Abstract: We want to understand how chromatin is organized in the human cell nucleus, how this influences gene expression, and how it is altered during normal development and in disease. A range of technical approaches (biochemical, biophysical and cytological) now allows us to analyse multiple levels of chromatin structure, from the nucleosome through to nuclear organisation. Combined with the use of genomic microarrays, this means that we can determine chromatin structures, not only at individual genes, but also across large regions of the genome. An example of the latter are Hox loci, which encode genes important for patterning of the developing embryo. To study how chromatin structures are changed during early embryonic development, we use the mouse as a model system, taking advantage of pre-existing models for Hox gene regulation. We have recently begun to uncover alterations in normal spatial genome organization in human diseases. As well as observing the way that the genome is normally organized, we have developed a method to experimentally alter the spatial organization of the human genome within the nucleus in tissue culture cells. We have used this system to show that recruiting genes to the nuclear periphery is sufficient to mediate their transcriptional repression. We suggest that spatial organization is used to regulate gene expression during mammalian development. Lastly, we complement our study of the organisation of DNA by analysing the function of specific nuclear proteins that are involved in chromatin structure and gene regulation, and that we have identified by gene-trapping in mouse embryonic stem cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Quantitative trait locus (QTL) identification in a Croatian isolate
Funder: Medical Research Council

Abstract: The aims of the study are, firstly, to genetically map and identify quantitative trait loci (QTL) influencing common human traits and disorders in isolated populations. We have performed whole genome association analyses in samples obtained from an epidemiological field survey of 1,041 individuals from the island of Vis on the Dalmatian coast of Croatia and a similar number from the island of Korcula. Our Croatian collaborators are currently sampling volunteers from the city of Split on the Croatian mainland. We propose to replicate and fine map the most significant QTL in other isolate and general population samples. Once this has been achieved, QTL will be identified by further genotyping and direct sequencing of candidate genes within each identified region. In addition, we propose to estimate the genetic parameters and analyse the distributions of the >100 quantitative traits (QTs) analysed to date. We are currently extending the field work by analysing further QTs (total of approximately 100) and harmonising the methods and choice of QTs with other members of the EUROSPAN FP6 consortium of isolate populations (Sweden, Netherlands, Croatia, Scotland, Italy). We have carried out a 320,000 single nucleotide polymorphism (SNP) whole genome scan in 2,000 members from the Croatian isolate, to carry out a QT genetic association study.


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

Abstract: Epigenetics describes the variation of gene expression that is not due to changes in the DNA sequence. It is an important process during animal early development for setting up and maintaining stable patterns of gene transcription in adult tissues. In essence it describes how modification of chromatin or DNA regulates a genes activity.||Our main interest is determining the interplay between chromatin and DNA based silencing mechanisms in maintaining gene silencing during early animal development? We have made some exciting discoveries establishing the importance of epigenetic regulators in determining the onset of transcription during early development in amphibians, and how mis-regulation of these processes may lead to apoptosis and subsequent alterations in cellular identity and development.||The maintenance cytosine methyltransferase, xDnmt1, is responsible for maintaining high levels of DNA methylation in development. We have shown that it also acts as a direct transcription repressor protein, independently of its catalytic function, in early embryos. In addition we have identified a potential pathway though which loss of xDnmt1 function results in direct activation of a cell death pathway.||We believe our findings have important implications for the molecular basis of diverse human diseases in which epigenetic regulation is altered and potentially an understanding of the nature of cellular potency (stem cells). Our work may also contribute to the development of safe health care applications such as small molecule inhibitors of Dnmt1 function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mouse Germ Cell Development
Funder: Medical Research Council

Abstract: Germ cells play a central role in genetics and inheritance to transmit genetic information from one generation to the next. However the way in which the germ cells do this differs between males and females. Differences between germ cell behaviour in male and female embryonic gonads are caused by sex-determining cues in the embryonic gonadal environment rather than by the intrinsic sex chromosome constitution of the germ cells themselves. The aim of this research programme is to identify the molecular nature of these signals, and how the germ cells respond to them.||We have identified an evolutionally conserved transmembrane protein, Sdmg1 that is expressed in the Sertoli cells of male embryonic gonads at the time of germ cell sex determination. In adult mice, Sdmg1 is associated with specialised secretory granules in secretory exocrine cells suggesting that this protein may have a role in membrane trafficking. RNAi-mediated knock-down of Sdmg1 in conditionally immortalised Sertoli cell lines results in perturbed membrane trafficking and impaired masculinisation of germ cells in organ culture, and RNAi-mediated knock-down of Sdmg1 in mouse embryos causes defects in germ cell masculinisation. This suggests that Sdmg1 mediates secretion of germ cell masculinising factors from the Sertoli cells. We aim to extend this work by attempting to identify molecules that require Sdmg1 for their secretion from Sertoli cells. We have also generated and are characterising Sdmg1 knockout mice.||One of the consequences of the germ cells sex determining decision for human genetics is that male and female germ cells tend to transmit different types of de novo mutations to the next generation. We have identified a novel genetic pathway operating in male and female mouse germ cells that helps maintain genetic and chromosomal stability through successive generations. We are currently investigating how this novel pathway operates, and whether it might contribute to the high rates of aneuploidy that arise during oogenesis in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: RNA processing and eukaryotic gene expression regulation
Funder: Medical Research Council

Abstract: Gene expression is extensively regulated at the post-transcriptional level. The fundamental steps of eukaryotic RNA processing have been characterised in great detail, but knowledge of how the disruption of these processes contributes to human disease has only recently begun to emerge. The major aim of this programme is to study the mechanisms for the post-transcriptional regulation of gene expression. Our laboratory studies different aspects of RNA processing, including alternative splicing regulation, microRNA processing and nonsense-mediated decay. The predominance of alternative splicing has become evident when completion of the human genome sequence revealed that a large proteomic complexity is achieved with a limited number of genes. We are particularly interested in the trans-acting factors that are involved in the regulation of alternative splicing, such as the SR proteins and hnRNP A/B type of proteins. These proteins have antagonistic activities and their molar ratio influence different modes of alternative splicing in vivo and may represent a mechanism for tissue-specific or developmental regulation of gene expression. We also study the subcellular distribution of RNA processing factors and how this could be affected by extracellular signals. The relevance of RNA processing, in particular pre-mRNA splicing, to human disease has emerged recently. Disturbances in pre-mRNA splicing have been found in a variety of disease processes. Splice site mutations are exemplified by some forms of thalassemia. However, in many cases, such as the dysregulated splicing of CD44 found in many human malignancies, mutations are not found in the target gene and it is presumed that the changes are due to changes in the milieu of splicing factors in the diseased cell. Therefore, cis-acting sequences and trans-acting factors that lead to aberrant RNA processing associated with human disease will be an important target of molecular therapies. Interestingly, pre-mRNA splicing is not only important to form the mature mRNA, that is exported to the cytoplasm, but also influences processing events that act downstream of it. Therefore, we have expanded our interest to RNA processing events that act downstream of pre-mRNA splicing, including nonsense-mediated decay and translational regulation. A combination of different methodologies is used in our research. We mostly rely on classical molecular biology and cellular biology techniques. Cell culture is widely used and we also are using two animal models, mice and the nematode C.elegans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Using signatures of mutation and selection in genome evolution to interpret contemporary genetic variation
Funder: Medical Research Council

Abstract: We are endeavouring to understand the processes of selection and mutation that are acting to shape genomes. It is well known that selection shapes the pattern of genomic changes that accumulate as populations diverge from a common ancestor. This has proven to be a very useful signature for the identification of functionally important regions of the genome. But it is becoming increasingly clear that fluctuations in the pattern of new mutations can also generate superficially similar signals. Improved separation of these confounding evolutionary signatures is crucial if we are to understand how organisms evolve, and to relate contemporary genetic changes to human biology and disease. The results of this research fall into three broad categories: (1) An improved understanding of mutational mechanisms - why and where particular types of mutation occur. This is of particular importance in understanding the progression of cancers and explaining why some genes appear to carry a higher detrimental mutational load in the population than others. (2) Better detection of both purifying and diversifying selection for the interpretation of function and relating functional genomic measures of the genome (e.g. chromatin, origins of replication, regulatory sequences) to evolution. (3) The development and application of methods to identify genes, pathways and biological systems enriched for deleterious mutations associated with human genetic diseases and cancer. These approaches build on established techniques from the field of evolutionary biology and can be applied to all genetic diseases.


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

Abstract: We investigate how cells take up large volumes of their medium into internal vesicles through macropinocytosis, and how they move towards attractive chemicals through chemotaxis. Both processes are highly conserved and use actin dynamics to shape projections from the plasma membrane. These projections either form a cup to engulf a droplet of medium or a pseudopod (or bleb) to move the cell forward. We have found that macropinocytosis in the amoeba Dictyostelium is regulated by the RasGAP, NF1. NF1 is a common human disease gene and tumour suppressor, but this is the first time it has been linked to macropinocytosis. We find that NF1 is targeted to macropinosomes and are trying to discover how this is achieved. Macropinosomes form around areas of intense Ras and PIP3 signalling in the plasma membrane that most likely act as a template for the characteristic cupped projections of macropinosomes. We seek to understand how this template works and the macropinocytic cups develop and close. The insights gained from amoebae are being extended to a range of human normal and cancerous cell lines. Dictyostelium cells chemotax towards cyclic-AMP and we have shown that this is controlled through a MAP kinase, whose role we are dissecting. Many cells can switch to an alternate mode of movement, based on blebs, when faced with mechanical resistance such as they experience in a tissue. Using a cell ‘squasher’ to impose load on cells, we have analysed the transition to blebbing motility in detail and identified a signalling process that may mediate it. For this work, we use molecular genetics, protein mass-spectroscopy, biochemical assays and advanced microscopy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Cell-autonomous and innate immunity
Funder: Medical Research Council

Abstract: Cell-autonomous defense is the oldest form of immunity and sufficient to protect unicellular organisms against infection. In multicellular organisms specialized sets of professional immune cells have evolved, whose activities have received much attention. Comparably little is known about the ability of individual mammalian cells to defend themselves against infection. Guided by the importance of cell-autonomous immunity as the sole defender of unicellular organisms, we investigate how mammalian cells protect their interior against infection.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Cell Biology of the Plasma Membrane
Funder: Medical Research Council

Abstract: The plasma membrane provides the key interface between a cell and its environment, and thus has a central role in a very wide range of cell processes. We are interested in the mechanisms underlying several important aspects of plasma membrane cell biology: particularly, how regions of the membrane are specialised for different functions, and how proteins and lipids are internalised from the membrane. We focus on the role of oligomeric protein assemblies that form specific microdomains. Caveolae, flask-shaped membrane invaginations formed by cavin and caveolin proteins, constitute one kind of microdomain, and flotillin proteins form another. Recent achievements have included revealing functions for flotillin proteins in cell migration, determining key protein actors at the neck of caveolae, characterising the large 80S protein complex that generates the bulb of caveolae, and quantifying flux through different endocytic pathways in tissue culture cells. Studies in cultured cells and model organisms have been successful in identifying many molecular components and specific protein-protein interactions. We now want to confront the complexity of how these components function in differentiated cell types. Our interests in caveolae and in endocytosis lead to projected experiments to elucidate the function of caveolae in the vascular system, and the membrane traffic mechanisms underlying vesicular transcytosis in endothelium. We will complement these experiments with biochemical and functional analysis of protein complexes at the neck of caveolae.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE