NIHRDataInsights/HRCSData huggingface dataset:
Title: Children's Growth during a Long-run Health Transition: Britain in International Perspective, 1850-1995
Funder: Economic and Social Research Council

Abstract: This project will explore how improvements in nutrition, sanitation, and medical knowledge during Britain's long-run health transition from 1850 onwards influenced children's growth pattern in terms of height, weight and BMI. Studying children's growth pattern (velocity of growth and shape of the growth curve) rather than their height at a specific age is a significant methodological innovation. Adaptive theories of human development and growth stress how exposure to poor nutrition or disease, especially in utero, does not merely affect the child's current height but also the timing of the pubertal growth spurt, their velocity of growth and the length of the growing period: in other words, their growth pattern. This project will extend existing knowledge of children's growth in Britain in three ways: first, by reconstructing boys' longitudinal growth measurements from training ship records spanning the century and a half from 1865 onwards; second, by producing and analysing new growth profiles from historical sources; and third, by placing the change in Britain's growth pattern in international context using growth profiles (the average height and weight of children across a number of ages) collected from 1850 to the present from around the world. Four new datasets will be produced and deposited in the UK Data Archive as a part of the project: three individual-level datasets with the heights and weights of children and a dataset with growth profiles for a wide range of countries around the world from 1850 to the present. The data produced will supply a longer-run perspective on the immediate and intergenerational factors influencing children's growth patterns in Britain and internationally and indicate how the shift from an unhealthy to healthy growth pattern took place. The data will also assemble new evidence on historical BMI growth curves and child obesity rates, providing historical context for the current child obesity crisis. The project's findings are particularly relevant to the current discussion about a post-2015 development framework to replace the Millennium Development Goals and to understanding the childhood obesity crisis and will inform health interventions and development policy goals for improving the health of children in both the developing and developed worlds. I am uniquely suited to carry out this research because I have conducted extensive research on historical children's growth and understand the potential problems that surround these data (Schneider, 2013a, 2013b). I have also developed substantial knowledge on the biology of human growth, allowing me to bring a necessary interdisciplinary approach to the project.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Does gender make you sick? Understanding and improving health from a comprehensive gender perspective.
Funder: Economic and Social Research Council

Abstract: Everyone has the right to a chance of a long life in good health, no matter whether they are a man or a woman, rich or poor. However, globally men (in both rich and poor countries) experience a higher burden of disease and have lower life expectancy than women. Much of this difference is due to men's risk-taking behaviours: they drink more alcohol, smoke more tobacco and drive more dangerously than women do. Some of this is driven by gender - i.e. the social rules and norms that tell each and every one of us what is appropriate behavior for men and women in all societies. Much of the current research on gender and health focuses mainly on women and girls and their health-related risks. We believe it is very important to understand and address the issues that globally place men more at risk of illness, disability and early death. This is important not only for the health of men, but also for women's health too - for example, there is increasing evidence that young women in many countries are now beginning to drink and smoke at similar rates to their male peers. There is also evidence that men's risk-taking impacts negatively on women's health and wellbeing. We plan to establish and strengthen a network of researchers, practitioners and health advocates, who are engaged with studying and acting to improve the health of both men and women around the world through a better understanding of gender and health issues. Over a period of 3 years, researchers and campaigners in Asia, Africa, the Middle East, the Americas and Europe will come together to deliberate and identify solutions to improve the health of populations in different parts of the world. These ideas will be shared and debated with both policy makers and the communities of men and women whose health outcomes we are hoping to improve. Seminars will be open to a wide variety of participants, and at least half the time the seminars will be web-based and hence available to all. We will communicate the outputs from the seminars through websites and social media, and hope that in doing so we can raise awareness that gender affects the behaviours, risks, and health of everyone, not just women and girls.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: An investigation of the quality of the scottish national dried blood spot collection and its suitability for use in genetic epidemiological studies
Funder: Chief Scientist Office (Scotland)

Abstract: Remarkable opportunities for exploiting neonatal dried blood spots (DBS) have recently emerged. The Scottish DBS collection covers virtually the entire population born after 1966, and through the NHS Information and Statistics Division can be linked to individual disorders. Our aim is to test the quality of the Scottish DBS and to develop the best protocols for extracting the proteins, DNA and RNA for use in future genetic epidemiological studies. Since DBS from 1966 to 1979 were autoclaved prior to storage, we will evaluate blood spots from each decade. The protein fraction will be assayed for a range of cytokines and immunoglobulins, and whole genome amplified DNA will be interrogated using microarray and sequencing technologies and patterns compared to those from lymphocyte DNA from the same individuals. Protocols to allow epigenetic studies will be also explored as will the feasibility of RNA extraction for neonatal expression profiling.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Palmitoylation of Exocytic Proteins: Role in Membrane Compartmentalization, Intracellular Trafficking, and Function
Funder: Medical Research Council

Abstract: The fusion of intracellular secretory vesicles with the plasma membrane (exocytosis) mediates cellular secretion of essential molecules such as neurotransmitters and hormones. Exocytosis in neuronal cells is dependent upon the interaction of the plasma membrane SNAREs, SNAP25 and syntaxin 1A, with the vesicle SNARE, VAMP2. Indeed, the formation of this ‘SNARE complex‘ may directly catalyze membrane fusion. A large number of other proteins function in exocytosis, including the chaperone cysteine-string protein (CSP). Despite a good understanding of the proteins and protein-protein interactions that mediate exocytosis, far less is known about how lipid modifications, such as protein palmitoylation, regulate this process. We identified a relationship between the number of potential palmitoylation sites in SNAP25, or its ubiquitous homologue SNAP23, and the extent of exocytosis. These effects of palmitoylation on exocytosis may be mediated by compartmentalisation of SNAP25/23 into specific micro-domains of the plasma membrane. To extend upon these novel observations, we will utilise mass spectrometry to analyze the extent of SNAP25/23 palmitoylation, and whether differentially palmitoylated pools of these proteins are present in cells. Immunogold labelling will then be used to precisely map the micro-localisation of SNAP25/23 at the plasma membrane, and determine how this is modulated by palmitoylation. Furthermore, we will examine the activity-dependent regulation of SNAP25/23 palmitoylation, and of other cellular proteins, and determine the importance of this for exocytosis. Finally, total internal reflection microscopy and amperometry will be used to pinpoint the aspect(s) of exocytosis that is modulated by specific SNAP25/23 cysteine mutants or palmitoylating enzymes. In addition to regulating micro-localization and function of SNAP25/23, we propose that palmitoylation also regulates the intracellular sorting of SNAP25 and CSP. Indeed, recent work has highlighted an important role for palmitoylation in the intracellular trafficking of certain proteins. However, little is known about how palmitoylated proteins that lack identifiable primary membrane targeting determinants, such as SNAP25 and CSP, are trafficked within the cell. To address this, we will use a combination of confocal imaging, fractionation and inhibitor studies to identify the intracellular trafficking pathways of SNAP25 and CSP, and determine how trafficking and correct sorting is regulated by palmitoylation. In addition, we will determine how palmitoylation code regulates correct intracellular sorting to specific pre/post-synaptic sites in neurons. Finally, the role of palmitoylation in regulating the exocytic function of CSP will be tested. Overall, these analyses will provide novel data on the role of palmitoylation in regulating protein trafficking, micro-localization and function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: CENTRE FOR DRUG SAFETY SCIENCE
Funder: Medical Research Council

Abstract: We propose to create a Centre for Drug Safety Science at the University of Liverpool, in collaboration with the University of Manchester, the MRC Toxicology Unit in Leicester, the Medicines for Healthcare products Regulatory Agency (MHRA) and Pharmaceutical Industry. This will provide a centre of excellence for research into drug safety, which is important because: (a) adverse reactions to drugs are common accounting for hospitalisations, visits to GPs and in some cases, patient deaths; (b) drugs continue to be withdrawn from the market because of safety concerns with adverse economic consequences and reduced expenditure on future R & D; (c) the number of new drugs coming onto the market has been poor over the last decade; and (d) the combination of drug withdrawals and lack of new drugs will adversely affect drug choice for patients. Our mission in the Centre will be to enhance drug safety by developing a facility that will enable research that goes from the laboratory bench to the patient bedside (and vice versa) to identify, evaluate and understand the fundamental mechanisms of adverse drug reactions. We have a 20-year track record of research in this area. The Centre will allow us to consolidate and strengthen this expertise, and will have an unrivalled breadth of research ranging from fundamental cellular processes through animal physiology and pathology to modelling and human population studies, inter-linked in a real sense to add value to research into drug safety science right through from molecule to man. We believe that with Centre status we will be able to compete at the highest levels internationally in undertaking translational research in drug safety for the benefit of patients, the public, the industry and regulators. We have several objectives for the Centre: (a) enhance the safety of medicines; (b) provide new knowledge that informs the design and development of medicines in the future; (c) provide an environment for collaboration between scientists from Academia, NHS, Government and Industry; (d) facilitate training for safety scientists from both clinical and basic backgrounds; and (e) provide impartial advice to all relevant stakeholders. Most importantly, we believe that a fundamental understanding of the mechanisms of adverse drug reactions will serve to inform the patient, the doctor and the medicinal chemist about the risk-benefit of new medicines and through this make drug therapy safer. This is the ultimate aim of our proposed Centre for Drug Safety Science.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms ensuring sister kinetochore bi-orientation on the mitotic spindle
Funder: Medical Research Council

Abstract: To maintain their genetic integrity, eukaryotic cells must segregate their chromosomes properly to opposite spindle poles during mitosis. This process mainly depends on the forces generated by microtubules that attach to kinetochores. For proper chromosome segregation, sister kinetochores must be captured by spindle microtubules extending from the opposite spindle poles, prior to anaphase onset; this state is called sister kinetochore bi-orientation. Using budding yeast as a model organism, we will study the molecular mechanisms that ensure sister kinetochore bi-orientation on the mitotic spindle. With live cell imaging and biochemical approaches, we will address how re-orientation of kinetochore-spindle pole connections proceeds and facilitates bi-orientation, and investigate how re-orientation is regulated by two mitotic kinases Aurora B (Ipl1 in yeast) and Mps1, major regulators for bi-orientation. Our research should contribute to understanding mechanisms for bi-orientation in human cells because basic mechanisms for chromosome segregation are well conserved from yeast to humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Analysis of regulation of telomerase action and telomere capping function by the telomeric complex.
Funder: Medical Research Council

Abstract: Telomeres ensure both the protection of chromosome ends and their complete replication by assembling a protein complex on terminal arrays of DNA repeats. The maintenance of these repeats is guaranteed by the telomerase enzyme, whose regulation is the result of a complex interplay between positive and negative regulators acting in cis at each telomere. Understanding how telomerase is preferentially activated at shorter telomeres, and inactivated at longer ones represents a fundamental problem, and one which has implications for human disease and ageing, as telomere erosion triggers cellular senescence and genome instability, and can act as a tumor-suppressor mechanism. Because telomerase activation appears to require transient uncapping of the telomeric complex during specific phases of the cell cycle, telomerase regulation and telomere protection are interconnected problems I will investigate how the telomeric complex modulates telomerase-accessibility and how it achieves its protected state. Using budding yeast as a model system, I will address how telomere length affects telomerase activity at individual telomeres. This will involve uncovering the structural transitions taking place in S phase, the time of telomerase action, at shortened telomeres leading to telomerase activation, and the mechanism(s) preventing these transitions at longer telomeres. This will be done in part using a system for the generation of a unique short telomere in yeast cells. In addition, I will use the regulated induction of double-strand breaks at chromosomes as models to investigate the molecular events leading to the early replication of short telomeres. In a different approach, I will aim to identify novel telomeric factors involved in telomere maintenance and protection. To this end I will use fission yeast both because of crucial technical advantages offered by this organism, and because findings are likely to be novel and to shed insights in human telomere biology. In fact, because the fission yeast telomeric complex appears to bear closer resemblance to the mammalian one in several respects, I will also conduct a screen targeted to identify fission yeast factors involved in telomerase recruitment. Finally, I will use imaging approaches in mammalian cells aimed at addressing whether the parent or daughter telomeric TG-rich strand (or both) act as substrates for telomerase action. In summary, the goal will be to address fundamental aspects of the functioning of the telomeric complex by working in three different systems using different methodological angles.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: An investigation of DNA repair processes during DNA replication using the archaeon, Sulfolobus, as a model organism.
Funder: Medical Research Council

Abstract: In all organisms, repair of DNA damage is critical to maintaining genomic integrity and therefore viability. Indeed, the loss of chromosomal stability is coincident with the development of many cancer related diseases (1, 2). The process of replication fork restart is central to the maintenance of normal genetic equilibrium (3). Illegitimate recombination and genomic instability can ensue following the defective repair of stalled replication forks. Unfortunately, the intricacy of replication restart pathways in metazoan organisms complicates direct experimental observation. I propose to elucidate the mechanisms of replication fork restart by taking advantage of the experimental tractability of the model organism Sulfolobus. By investigating the clear archaeal orthologues of eukaryotic repair proteins, I am optimistic that the general themes observed in this study will aid our comprehension of eukaryotic DNA replication associated repair processes. The overall objective of this investigation is to understand how replication forks are stalled and restarted in the hyperthermophilic archaeon Sulfolobus, and relate the findings to eukaryotic systems Specifically, I aim to improve our understanding of the macromolecular assembly of higher-order structures at stalled replication forks. Biochemical, structural and genetic approaches will be adopted to examine the interactions that underlie these critical fork restart mechanisms Initially, yeast two-hybrid and co-immunoprecipitation approaches, using candidate repair proteins that have been implicated in restart processes, will be performed to identify novel proteins and complexes associated with replication fork restart. Subsequently, the DNA binding preferences and metabolism of these candidate restart/repair complexes will be investigated by biochemical assays, using synthetic DNA substrates mimicking replication forks and repair-associated structures. Collaborations will be developed to examine the structural basis of the most interesting interactions. Finally, the in vivo significance of these associations will be analysed in Sulfolobus cells using genetic approaches involving the generation of domain specific mutations of the candidate proteins. Ultimately, I am confident that this study will provide valuable insights into the structure and function of the protein complexes involved in eukaryotic replication fork restart mechanisms 1. Thompson, L. H., and D. Schild. 2002. Recombinational DNA repair and human disease. Mutat Res 509:49-78. 2. Hickson, I. D. 2003. RecQ helicases: caretakers of the genome. Nat Rev Cancer 3:169-78 3. Branzei, D., and M. Foiani. 2007. Interplay of replication checkpoints and repair proteins at stalled replication forks. DNA Repair (Amst).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of Developmental Gene Expression through Control of Transcriptional Elongation
Funder: Medical Research Council

Abstract: Control of gene expression is crucial for the development and survival of all animals. Incorrect gene expression can lead to death or severe abnormalities during development, and in adult life may cause cancer. Recently, transcription elongation has become recognised as a critical point of control during the expression of many genes during development. For example, half of the genes that initiate transcription do not produce detectable transcripts in human embryonic stem cells, indicating that there is widespread inhibition of transcript elongation (Guenther et al., 2007, Cell, 130:77-88). Aberrant regulation of transcriptional elongation has been implicated in a number of human diseases including acute myeloid leukaemia (Conaway, J. W. & Conaway, R. C., 1999 Annu Rev Biochem, 68:301-19). Little is known about how contextual cues are integrated by proteins in the elongating polymerase complex to modulate transcription. However, two factors that interact with the polymerase have been implicated in gene-specific control of elongation; Spt5 and Negative Elongation Factor (NELF; for a recent review of the field see Saunders et al, 2006, Nat Rev Mol Cell Biol, 8:557-67). The aim of this proposal is to ascertain the molecular mechanisms regulating transcriptional elongation in response to developmental cues. My central questions are: Which factors are involved? How do these factors interact with each other and RNA polymerase? To address these questions, I will both analyze known regulators (Spt5 and NELF) and identify novel factors, using developmental regulation of gene expression in drosophila as a model system. The known key regulators of transcriptional elongation in humans are conserved in drosophila. I will exploit the many technical advantages of drosophila (including genetic tractability, vast collections of mutants, fully sequenced genome with mature annotation, short generation time, and externally laid eggs) to analyze the roles of Spt5 and NELF during development in vivo. In parallel, I will use a combination of yeast two-hybrid and biochemical assays to characterize interactions between Spt5, NELF and candidate regulators, and to screen for novel factors regulating transcriptional elongation. The results from my research will extend our knowledge of the fundamental process of transcription and will impact on studies of gene expression, developmental biology and stem cells. Furthermore, understanding the mechanisms mediating gene-specific control of transcriptional elongation will help to identify key regulators, possible pathways of mis-regulation and potential targets for future pharmacological intervention in cancers.


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