NIHRDataInsights/HRCSData huggingface dataset:
Title: Effective and efficient conduct of trials and meta-analyses
Funder: Medical Research Council

Abstract: There is an urgent need for new methods for many clinical studies. One challenge is finding cost-effective, evidence-based methods for running trials. This increases the likelihood of producing reliable results in a timely manner, which in turn frees resources to allow more trials to take place. We will do this by developing and evaluating methods for ensuring that trials are run effectively and efficiently. We are providing practical examples of how novel designs can be implemented; evaluating and implementing strategies to ensure that data quantity and quality are maximised and that staff time locally and at sites is best used. We are also investigating how to get trials started and reported more quickly, and to make appropriate use of e-health resources. Gains from efficient conduct may be dissipated or lost completely if evidence synthesis of trials is protracted, inefficient or poorly conducted. Furthermore, if understanding or use of systematic reviews is limited, then clinical practice and research may not be informed by the best evidence. We will address these issues by developing a new framework for meta-analysis to speed up the evaluation of individual therapies; providing tools and guidance to promote greater awareness, understanding and use of IPD meta-analysis across a variety of stakeholders and resolving outstanding issues in systematic review conduct.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: China Kadoorie Biobank (CKB) prospective study of 0.5 million adults
Funder: Medical Research Council

Abstract: China Kadoorie Biobank is a blood-based prospective study of 512,000 adults, recruited during 2004-8 from 10 diverse regions of China, with extensive data collected at baseline and subsequent resurveys using questionnaires, physical measurements, and stored biological samples. Chronic diseases are major causes of death and disability in China and worldwide. Large-scale prospective studies of multiple risk factors, with blood storage for testing novel hypotheses and detailed follow-up of health outcomes, will help assess the causes of chronic diseases. Studies in China, given the special patterns of exposures and diseases, will yield novel findings, complementing similar studies elsewhere (e.g. UK Biobank). The CKB will improve understanding of disease aetiology, risk prediction and the development of new therapies, benefitting populations worldwide. By Q4 2016, follow-up through linkage to death and disease registries and to nationwide health insurance databases of all hospitalised events has accumulated 0.5 million hospitalised events and 35,500 deaths among CKB participants, including incident cases of stroke (42,000), IHD (35,000), cancer (23,000), diabetes (13,500) and COPD (9,500). Only ~4,000 (<1%) participants were lost to follow-up. Genome-wide data are being generated (first phase: ~100,000 participants by Q3/2016), along with blood biochemistry and multi-omics data for nested case-control studies of specific diseases. CKB will prioritise (i) continued follow-up of cause-specific morbidity and mortality and hospital records through electronic linkage to health insurance systems; (ii) validation, clinical adjudication and detailed sub-phenotyping for selected diseases (e.g. stroke, IHD, cancer); (iii) maintenance and management of extensive and uniquely large and complex datasets; (iv) enhancement of collaboration and data sharing with the wider scientific community. Future research based on data and samples collected to date is likely to lead to the identification of novel genetic and blood-based biomarkers involved in various chronic diseases. These can help develop improved algorithms for disease risk prediction. Biomarkers associated with early onset and/or progression of disease may also be used for early diagnosis and prediction of prognosis. Improved understanding of disease pathways and mechanisms may lead to the identification of novel therapeutic and pharmacogenetic targets that may be patentable or commercially exploitable. Health insurance data already collected (2006-2016), includes 600,000 coded hospitalised disease events of many different types and 60 million in-hospital treatment, test and procedures-related data. Analysis of this will help evaluate the delivery of effective healthcare by quantifying over-hospitalization and inappropriate use of investigative procedures and treatments for common causes of hospitalizations.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Randomized trials in cardiovascular and metabolic diseases
Funder: Medical Research Council

Abstract: The aim of this programme is to generate reliable evidence about interventions with the potential for significant public health benefit. Treatments with even modest effects in common diseases (such as cancer, cardiovascular disease, diabetes, chronic kidney disease or osteoporosis) may make significant contributions to reducing morbidity and mortality globally. Building on epidemiological evidence generated in PHRU and elsewhere for associations between various biomarkers or risk factors (e.g. lipid markers, 25(OH) vitamin D), we aim to deliver large-scale randomised evidence to determine whether such associations are causal and reversible. Along with smoking and blood pressure, blood lipids are a major cause of cardiovascular disease, a major cause of morbidity and mortality worldwide. Higher levels of LDL cholesterol and lower levels of HDL cholesterol are associated with higher risks of coronary heart disease. Partly as a result of a series of large randomised trials (HPS, SEARCH and SHARP run by PHRU) and meta-analyses (also conducted by PHRU), statins, which effectively lower LDL cholesterol, are now very widely used for the primary and secondary prevention of cardiovascular disease. However, although widely used, available and highly cost-effective some patients remain at high risk despite statin use, thus additional safe treatments to modify risk are needed. Attention is now turning to newer drugs which modulate lipids by other mechanisms. The effects of such additional treatments on top of statins are likely to be modest, so large-scale randomised evidence are required to assess their effects reliably, hence the REVEAL trial of a cholesterol ester transfer protein inhibitor (CETPI) anacetrapib has randomized 30,000 people worldwide at risk of cardiovascular disease. Over the last several years, PHRU has developed streamlined methods to recruit large numbers of patients and conduct trials efficiently (e.g. REVEAL) as well as cost-effectively (e.g. ASCEND), including using factorial designs to address more than one question at a time and using record linkage to facilitate follow-up, both during the trials (e.g. ASCEND, 3C, LENS) and in the longer-term (e.g. HPS, SEARCH). In addition, PHRU has piloted trials of non-commercial questions (e.g. high-dose vitamin D in older people) and of a combination of angiotensin receptor blocker and neprolysin inhibitor (ARNI) in chronic kidney disease with a view to securing funding for larger trials aiming to generate reliable evidence. Dementia and other neurodegenerative diseases are also major causes of public health problems, and incur huge costs for families and health and social services, but they have been relatively poorly researched. Collaborating with other researchers, MADE and Schizophrenia ATLAS in neurodegenerative diseases will help answer important clinical questions and help build collaborations for the future.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Genomic imprinting and the epigenetic control of developmental processes
Funder: Medical Research Council

Abstract: Genomic imprinting is an epigenetically regulated process causing genes to be expressed according to their parental origin. Genetics studies have shown that genomic imprinting occurs at dosage-sensitive genes and regulates important developmental processes during the lifetime of the mammal. In human, altered imprinted gene expression is associated with growth, metabolic and neurological disorders, and cancer. Imprinting is regulated by DNA methylation, an epigenetic modification that differentially marks the two parental chromosomes influencing long range cis-acting control of the activity and repression of protein-coding and small and large regulatory non-coding RNAs. Over the past 20 years, genomic imprinting has emerged as a useful paradigm contributing to our understanding of the roles of epigenetic modifications in the regulation of gene activity and repression, and into wider mechanisms underlying the epigenetic control of genome function in development, health and disease. Recently we have shown in a developmental model of postnatal neurogenesis, selective absence of imprinting occurs to control gene dosage in the stem cell niche and this is required to maintain the postnatal stem cell pool and the synthesis of new neurons. This suggests that dosage control by imprinting may be an epigenetically modulatable process that can adapt to particular environmental requirements during development. Understanding epigenetic modulation in response to environmental signals is a major challenge in biomedical research. The proposed research aims to focus on mechanisms and developmental pathways associated with this. Addressing these aims has timely general implications for understanding the epigenetic regulation of the stem cell niche and for the characterization of factors and pathways that influence the relationship between stem cells and their environment contributing to our understanding of adult onset diseases, neuronal plasticity, aging and cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Modeling of wound repair and inflammation in the Drosophila embryo
Funder: Medical Research Council

Abstract: Drosophila embryos provide a model of wound healing and the associated inflammatory response that is both genetically tractable, and amenable to live, high resolution imaging of these very dynamic processes. This combination of genetics and live imaging is very powerful for uncovering the mechanisms that underpin repair and is not available in other model organisms. We have established a laser wound model that allows us to observe both the wound re-epithelialisation response and the associated recruitment and resolution of inflammatory cells to and from the wound. We will use a variety of well tested Drosophila genetic techniques, in particular the GAL4 UAS system to drive various fluorescent gfp and/or mCherry fusion proteins in either epithelial cells or hemocytes (Drosophila macrophages) to track the dynamic behaviours of actin, or microtubules or junctional proteins during the healing process. The same system will be used to drive reporters (eg of Calcium or H202) or RNAi constructs to knock down genes in specific tissues. We also propose several microarray experiments using the FlyChip facility in Cambridge to analyse the transcriptional changes following wounding and/or bacterial infection as well as genetic screens which will take advantage of publically available p-element insertion lines. Our standard tool for imaging the wound response in wild type embryos or in embryos where a component has been genetically or pharmacologically modified, will be live confocal microscopy using both conventional confocal microscopes together with spinning disk confocal microscopy. Complementary TEM studies will also be used where understanding of ultrastructure is important also. Our work will also take advantage of a bead implantation assay developed in our labs which allows local application of pharmacological reagents to wounds and subsequent live imaging. This technique opens up a wealth of experimental possibilities as outlined in the case for support.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding the regulation and topological organisation of DNA in the human genome
Funder: Medical Research Council

Abstract: Chromatin plays a key role in maintaining genome integrity, regulating nuclear processes and affects human diseases including cancer. We have recently developed an assay for mapping high resolution DNA topology and discovered that DNA in cells is organised into DNA "topological domains" consisting of over and under wound DNA. We hypothesise these are important for regulating gene expression, replication and chromosome stability, and can influence higher levels of chromatin organisation. The aim of this programme is to investigate these domains in the human genome using a combination of molecular biology approaches. We will map their structural organisation in different cell types and investigate how they are related to gene expression. We will also identify the molecular processes, such as gene transcription and topoisomerase activity, that regulate their structure and the molecular mechanisms that promote their formation. By activating gene expression we will study how topological domains are propagated throughout the genome. To investigate how topological domains influence gene expression and activation, we will use an inducible reporter gene assay to give an insight into why genes are clustered in the genome. Common fragile sites (CFS) are regions of the genome that have a propensity to become unstable during replication stress. We will investigate the DNA topology and chromatin structure of CFSs to identify the basis for their instability and determine if their DNA topology is refractory to replication. We will also assess whether the topological environment at CFSs is linked to transcription and assess whether fragile site formation is caused through polymerase collisions. These studies will reveal a new fundamental property of the human genome that is important for regulating nuclear processes and will provide a molecular understanding for some of the most common chromosomal aberrations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of spindle checkpoint silencing
Funder: Medical Research Council

Abstract: The spindle assembly checkpoint is the prime cell cycle control mechanism that ensures sister chromatids are bi-oriented before anaphase takes place. Components of the checkpoint include the Mad1, Mad2, Mad3(BubR1) and Bub3 proteins and the Bub1, Mph1(Mps1) and Aurora B kinases. The checkpoint is activated when individual kinetochores are not bound to microtubules or not under tension. Upon activation at the kinetochore Mad2 and Mad3 bind to and inhibit Cdc20, an essential activator of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase. When the checkpoint is satisfied the spindle checkpoint signal is silenced and the Cdc20-APC/C is activated. This triggers polyubiquitination of securin and cyclin, which allows the dissolution of sister chromatid cohesion and mitotic progression. Although components of the checkpoint were identified 20 years ago, their binding sites at kinetochores are largely unknown. Moreover, the molecular mechanism(s) by which the spindle checkpoint is switched off following chromosome bi-orientation are not well understood. We have recently made two important advances in this field using fission yeast as a model system. Firstly, we have found that association of type 1 phosphatase (PP1) to both the Spc7 kinetochore protein and to kinesin-8 motors are necessary to silence the spindle checkpoint. Secondly, we have found that phosphorylation of Spc7 by Mph1 recruits the Bub1 and Bub3 checkpoint proteins to kinetochores to enable spindle checkpoint signalling. We are now in an excellent position to 1. To determine how silencing of the spindle checkpoint is triggered. 2. To elucidate the critical downstream targets of PP1 that mediate checkpoint inactivation. 3. To determine whether these mechanisms are conserved in human cells. We will use a variety of techniques including molecular genetics, biochemistry, mass spectrometry and fluorescence microscopy in both fission yeast and human cells to address these questions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: MICA: Health e-Research Centre
Funder: Medical Research Council

Abstract: The Health e-Research Centre (HeRC) will turn under-used electronic health data in Northern England into new knowledge and improved healthcare. The data sources include NHS and health science databases. HeRC will develop and apply Health Informatics (HI) methods to harness these disparate data sources through three streams of work: 1) researching and developing HI methodology to make linked health data more available for analysis; 2) applying HI methodology to solve previously intractable health science and service questions; and 3) training a new cadre of health informaticians to drive the methodology and its support of cutting-edge research. In contrast to data captured purely for research, data generated during healthcare are incomplete, inaccurate and subject to variation in recording. HeRC will develop ways to improve data capture, including patient reported outcomes, and to handle variations in recording. Questions researchers face when using health records will be addressed, e.g.: Which data are available and where? Do I have permission to use the data? What can I learn from other who used similar data? Software will be developed to provide a research environment that embeds key methods so that they can be learnt and used. The research environment will also embed datasets, making them discoverable, whilst maintaining high standards of information governance. Five research programmes will apply HeRC's methodology to cutting edge uses of linked health data across a spectrum of public health, clinical and health policy problems. To deliver HeRC, the consortium will integrate Northern England' leading centres for statistics at Lancaster, public health at Liverpool, computer science at Manchester, and health economics/services research at York. This integration will extend to the NHS, building on a promising model (NHS e-lab) of patient, public and community involvement in the trustworthy reuse of health data for research.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms regulating spindle formation and chromosome segregation in human cells
Funder: Medical Research Council

Abstract: The aim of my lab's research is to understand the mechanics and regulation of cell division and chromosome segregation. Aneuploidy, the condition where chromosomes are either lost or gained, is a consequence of faulty chromosome segregation and is considered both a hallmark and a driving force for tumorigenesis. A better appreciation of the processes ensuring accurate chromosome segregation may therefore lead to novel therapeutic approaches for cancer. While many molecular players contributing to the formation of the mitotic spindle and kinetochores have been identified, the precise biochemical activities of these components and how they are dynamically regulated throughout mitosis is often not understood. Our goal is to integrate the identification of components contributing to mitotic progression with the characterization of their biological function, exemplified by our recent identification of the astrin-kinastrin spindle and kinetochore complex as a novel microtubule plus-end tracking activity. In addition, we are interested in the control of mitosis by post-translational modifications (PTMs) such as phosphorylation and acetylation. Many enzymes involved in the dynamic regulation of these PTMs remain still to be discovered as highlighted by our recent identification of the PP6 phosphatase as the mitotic T-loop phosphatase for the Aurora A kinase. We now propose to study three related areas critical for chromosome segregation: 1.) The regulation of spindle formation and chromosome segregation by mitotic phosphatases, 2.) The regulation of stable microtubule kinetochore attachment formation by microtubule plus-end tracking complexes and post-translational modifications and 3.) The regulation of mitotic progression by reversible acetylation. To address these research themes we will use a combination of biochemical and cell biological techniques, using both cutting edge mass spectrometry and imaging techniques as well as classical biochemical approaches.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Roles of ubiquitin and SUMO during chromosomal DNA replication.
Funder: Medical Research Council

Abstract: Post-translational modification of proteins by members of the ubiquitin family: specifically ubiquitin and SUMO, is essential in DNA damage response pathways. However their role during unperturbed DNA replication not well understood. The initiation stage of DNA replication depends on ubiquitin-mediated proteolysis. However, a growing body of evidence suggest that the further stages of DNA replication are also regulated by these modifications. The importance of ubiquitin/SUMO ligases during unperturbed DNA replication has been shown, but very little is known about their substrates. My aim is therefore to use my experience in studying protein complexes assembled during DNA replication to investigate their regulation by ubiquitin and SUMO. For the first part of my project I will use the cell-free Xenopus egg extract system, which provides a powerful system for the biochemical analysis of eukaryotic chromosomal replication. I will identify proteins ubiquitylated and sumoylated during DNA replication by mass spectrometry analysis. I will then select most interesting candidates and map the modifications sites and their function during DNA replication. My preliminary data suggest an important role for polyubiquitylation in the disassembly of the replisome upon termination of DNA replication forks. These findings are of the highest interest as at present we have little knowledge of this process. I will, therefore, study the mechanism and the consequences of this defect. I will also investigate the effects of blocking sumoylation on replisome formation, regulation and disassembly. Once novel ubiquitylated and sumoylated proteins have been identified and basic mechanistic studies have been performed using Xenopus egg extracts I will select a few most interesting substrates and study their modifications in human cell lines.


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