NIHRDataInsights/HRCSData huggingface dataset:
Title: evolutionary conservation of group B Sox function in Drosophila.
Funder: Wellcome Trust

Abstract: The primary aims of the project are to: 1) perform a comparative in vivo analysis of the genomic activity of two closely related Sox domain transcription factors in four different Drosophila species; 2) determine the evolutionary conservation of the regulatory network driven by the Sox factor Dichaete in neural cells; 3) investigate the conservation in genome wide chromatin accessibility profiles across 4 species of Drosophila.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Sheffield Human 3T MR Imaging & Spectroscopy Facility.
Funder: Wellcome Trust

Abstract: Magnetic Resonance Imaging has undergone rapid development since its inception in the 1970 s. The emphasis of development has shifted from anatomical pictures to images of function. We were one of the first centres in the UK to install a clinical 3T neuroimaging system, seven years ago and we have reported results of studies that have benefitted from its added 'high-field' value. Technical advancements are still very proliferative and state-of-the-art MR systems marketed by the main manufacturer s have changed substantially over seven years. To continue developments, clinical applications and basic science investigations, we are seeking to procure a new 3T MR system with the help of partial funding from the Wellcome Trust. Sheffield s MR imaging team has a reputation and strong commitment for developing novel techniques and applying them to clinical problems We plan to extend our world-leading role in gas imaging of the lungs and heart function and crucially marry these with imaging of brain physiology and function. Ongoing specialisms include how diabetes effects the brain as well as how auditory hallucinations happen, how we can predict when cancer requires brain surgery before it becomes life-threatening and what we have to do to control the painful side-effects of chemotherapy.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: The specification of left-right symmetry in the nervous system.
Funder: Wellcome Trust

Abstract: Our nervous system, like our body, is bilaterally symmetric. The left-side of our brain is a near mirror image of the right side. This gives us many behavioural advantages in both sensing and responding to the external environment. For example, we are able to judge distance and discriminate the direction a particular sounds is emanating from. Disruptions in this bilateral organisation of the human brain are frequently observed in schizophrenia and epilepsy. The generation of neurons from a f ertilised egg requires a cascade of molecules that act within cells to push them towards a neuronal fate, rather than say becoming a muscle cell. However, this cascade is not fully understood. Because the genes that specify these molecules are similar in many organisms we can study them in animals that can be genetically manipulated such as the nematode C. elegans. The goal of my research is to identify new components of this cascade, crucial for developing neurons and establishing a bilateral ly symmetric nervous system. A better understanding of these genes will allow us to more easily generate specific types of neurons which can be used in transplantation therapies and will enhance our understanding and prevention of human neurological disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Mechanisms of endogenous analgesia.
Funder: Wellcome Trust

Abstract: Substantial evidence suggests the brain can reduce or switch off pain in certain circumstances. Understanding this natural pain suppression system is a major goal of translational pain research, and the proposal describes experiments designed to explain why and how such pain modulation occurs. First, we know expectations have a strong role in determining what we feel (as in the placebo effect), but there are different theories as to why and how this occurs. My first experiment manipulates pai n expectancies in healthy subjects, and tests different theories using behavioural modeling and functional brain imaging. Second, we think that there is a separate system, whereby the brain switches off pain when we actively escape g from situations of danger. This provides a survival advantage, but there are different theories of why and how the brain decides to activate the system. I will test these competing theories in a pain-escape task in healthy subjects. Finally, to obtain robust evidence to see if these systems utilise the brainstem pain suppression system, I will test whether they can be augmented by stimulating the brainstem in pain patients with implanted electrodes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Molecular and functional investigation of distinct pluripotent states in humans.
Funder: Wellcome Trust

Abstract: The greatest promise of induced pluripotent stem (iPS) cell technology is the potential to study human diseases in the Petri dish and to establish novel therapies for transplantation medicine. However, major challenges need to be overcome before human iPS and embryonic stem (ES) cells can be used in a realistic and efficient way for disease research. While mouse ESCs are well-characterized following three decades of research, the biology of human ESCs is fundamentally different and their develop mental potential is more limited than that of mouse ESCs. This research builds on recent success in converting conventional human ES or iPS cells into a 'naive' pluripotent state resembling classical mouse ESCs. I will develop robust procedures for generation and propagation of genetically unmodified human iPSCs that have the same biological characteristics as naive mouse ESCs. This may enable defining the developmental and therapeutic potential of patient-derived iPSCs by stringent criteria tha t are available only in the mouse system. The long-term goal of this project is to establish a novel platform of pluripotent human cells that may significantly facilitate the investigation of human diseases and the validation of potential therapeutic strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Elucidating the role of autophagy in protecting against prions.
Funder: Wellcome Trust

Abstract: Autophagy is a key pathway that degrades damaged organelles, long-lived proteins and toxic protein aggregates and is conserved from yeast to humans. The autophagy pathway is controlled by a group of autophagy related genes (ATG). Prions are self-propagating and infectious protenaiceous entities that causes several neurodegenerative diseases in mammals. Studies have demonstrated that autophagy protects againsts protein aggregation disease including prion disease. However, the mechanism of prion clearance and degradation via autophagy and the effect of defective autophagy towards prion formation are not well characterized. Oxidative stress is considered a causal factor in prion formation and is known to induce autophagy. Specific goals of this project are: i) to elucidate the role of autophagy in protecting against prion formation/accumulation using autophagy mutants and pharmacological induction. ii) to characterize the link between oxidative stress and autophagy towards prion formation using antioxidant mutants and exposure to exogenous ROS sources. iii) to investigate all of the above in the context of ageing Findings from this study will provide a more comprehensive understanding of the autophagy pathway in protecting cells against prions and may identify potential molecular candidates for use as therapeutic targets in combating prion diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Characterisation of the calcium-signalling pathway involved in the control of temperature-dependent locomotion by NCS-1 in C. elegans.
Funder: Wellcome Trust

Abstract: Many aspects of Ca2+ signalling are well characterised, such as control of intracellular Ca2+ concentration and the generation of Ca2+ signals but the downstream events that link changes in Ca2+ concentration to physiological function are less understood. Ca2+ signals regulate many aspects of cell function through Ca2+ binding to EF hand-containing Ca2+ sensors that then bind target proteins to regulate their function. Amongst the sensors are the neuronal calcium sensor (NCS) proteins involved in multiple neuronal signalling pathways. Each NCS protein has specific targets and physiological functions. This project will focus on the physiological function of NCS-1 using the model organism C.elegans. We have established a functional role for NCS-1 in temperature-dependent locomotion (TDL) behaviour in the worms. Expression of NCS-1 in only the AIY neurons is sufficient for regulation of that behaviour. We hypothesise that NCS-1 expressed in AIY neurons links Ca2+ to changes in organism behaviour and does so through interactions with specific target proteins that modify signalling within the thermosensory neural circuit. We aim to characterise the Ca2+ signalling pathway in AIY neurons that responds to temperature elevation by analysis of changes in Ca2+ concentration, kinetics of NCS-1 activation and determination of the downstream target(s) for NCS-1.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Mechanisms of cell death caused by Neurotrophin receptor expression.
Funder: Wellcome Trust

Abstract: Our aim is to elucidate the mechanisms by which the neurotrophin receptors TrkA and TrkC act as dependence receptors, i.e. induce the death of neurons inthe absence of their ligands Nerve Growth Factor and Neurotrophin-3 respectively, whilst TrkB does not induce cell death either in the presence ofabsence of Brain Derived Neurotrophic Factor (BDNF). To achieve this we will use mouse embryonic stem cells (mESCs) that have been engineered to conditionally express wild-type, mutant or chimeric forms of TrkA, TrkB or TrkC. These will be used to generate: neurons, non-neuronal cells such as stemcells, progenitors and oligodendrocytes/Schwann cells. These models will then be used to: a) characterise the effects of conditional TrkA-C expression in the presence and absence of their respective ligands and test their death-inducing potential in cells others than neurons, and b) identify the pathways involved in TrkA/C-induced cell death. To identify candidate molecules involved in TrkA/C-induced cell death, gene expression analyses will be carried out. Additionally, to identify the sub-domain(s) of TrkA that are involved in cell death, mESC lines expressing chimmeric or mutant TrkA receptors will be generated and used to form mouse embryos or primary culture of hippocampal neurons.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Characterising the temporal control of gene expression in Drosophila neural stem cells.
Funder: Wellcome Trust

Abstract: The aim of this project is to investigate the mechanisms controlling the competence of neural stem cells as they mature. In the developing Drosophila optic lobe, neural stem cells transition through a temporal cascade of six transcription factors that determines the birth order of the neuronal progeny. Strikingly, during the final transition of the temporal cascade, the neural stem cells switch from producing neurons to glial cells but the molecular mechanisms controlling this important competence transition are not known. To investigate the targets of the transcription factors, I will profile the binding sites of each transcription factor throughout the genome using a technique called Targeted DamID (TaDa),


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Focussed ion beam and scanning electron microscope for 3D reconstruction of large volumes in neuro- and cell biology and nano engineering of electron cryotomography samples.
Funder: Wellcome Trust

Abstract: We are proposing to acquire a FIB/SEM dualbeam instrument at the MRC Laboratory of Molecular Biology in Cambridge (LMB). LMB will provide dedicated, newly fitted-out facility space, staff support, a service contract and half of the instrument cost. Access of the wider community is ensured through the inclusion of Cambridge University's imaging centre and our dedication to make up to 30 % of time available to outside users. The focussed ion beam (FIB) is exceptionally useful for the removal of ma terial from samples for subsequent electron microscopy, at sub 5 nm resolutions not achievable by any other means. The machine will have two principal uses: firstly, the FIB will be used to serially remove very thin layers from large blocks of embedded tissues, with the electron beam producing images of each layer. This will allow automatic three-dimensional reconstruction of large volumes of whole tissues, making it possible to trace neurons and their connections or sub-cellular membrane domain s (FIB/SEM 'slice-and-view'). Secondly, milling of samples for electron cryotomography will enable us to visualise the interior of cells at isotropic resolutions approaching individual molecules and this application of the instrument will make heavy use of LMB's recent investment in high-resolution electron cryomicroscopy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Measuring and modelling the 'spillover' effects of healthcare interventions
Funder: Medical Research Council

Abstract: Aim To estimate the ‘spillover‘ impact of the patient‘s health condition on unpaid carers and to develop econometric models to forecast these impacts for use in economic evaluation. Objectives Phase 1: Validation of outcome instruments to measure the spillover impact in carers. Phase 2: Measurement of the extent of spillover impacts on carers using trial and survey data. Phase 3: Disentangling the spillover impact to distinguish between the ‘caring‘ and ‘family‘ effect. Phase 4: Econometric modelling of spillover impacts for future use in economic evaluation. Design/Methodology Phase 1: Tests of the validity and sensitivity of a new measure of ‘care-related‘ quality of life (the Carer Experience Scale) will be conducted using existing survey data from the UK, Australia and the Netherlands and data from a trial of drugs for Parkinson‘s disease (PD trial). Phase 2: Longitudinal data on outcomes for carers in the PD trial and carers of meningitis survivors (MEN study) will be collected using standardised instruments. The data will be used to explore how spillover impacts differ by illness, patient health state and hours of care provided. The analysis will be extended, where possible, by incorporating carer outcome data from other studies and outcome data for non-caring family members. Phase 3: Data from the MEN study will be used to identify the degree to which carer health is affected by the caring tasks undertaken as opposed to the patient‘s health condition. These ‘caring‘ and ‘family‘ effects will be estimated using regression models with the carer‘s health (and wellbeing in the second model) as the dependent variable and patient health, the number of caring tasks and other contextual characteristics of the caring situation as independent variables. Phase 4: Econometric modelling will be used to develop predictive models of the spillover effects of poor patient health. Data will be synthesised from different sources, where feasible, to estimate regression models with the carer‘s quality-adjusted life year (QALY) change as the dependent variable and a range of variables such as patient QALY change, hours of care and nature of patient disease as independent variables. Scientific and medical opportunities By identifying spillover effects and developing regression models to forecast these, this research will promote: (i) improved adherence to economic evaluation guidelines and (ii) decisions that come closer to maximising health benefits from available resources. This work will further explore the potential for using econometrics to estimate spillover impacts for economic evaluation.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL;INFECTION
Title: Molecular mechanisms of O-GlcNAc signalling.
Funder: Wellcome Trust

Abstract: Post-translational modification of eukaryotic protein serines/threonines with N-acetylglucosamine (O-GlcNAc) was discovered 20 years ago. Subsequent work has shown that O-GlcNAcylation is regulated by a tranferase (OGT) and a hydrolase (OGA), both single, essential genes, conserved from C. elegans to humans, and that a plethora of proteins in the nucleoplasm are O-GlcNAcylated. Excitingly, there are examples of O-GlcNAcylation having interplay with phosphorylation, including competition for the same serines/threonines, giving rise to the Yin-Yang hypothesis , that proposes O-GlcNAc as a global, glucose dependent, mechanism to control protein phosphorylation. I aim to use a multi-disciplinary approach to uncover the molecular mechanisms governing O-GlcNAcylation and its importance in a number of signal transduction pathways. Capitalising on a significant body or preliminary data, the aims are to: 1) Synthesize/discover OGA/OGT inhibitors and substrate analogues, including glycopeptide s. 2) Determine the structures of human OGA/OGT, including inhibitor/protein substrate complexes and probe mechanism/specificity with mutagenesis and in vitro assays. 3) Understand the effect of O-GlcNAc on phosporylation/activity on key signalling proteins in pathways involve in the insulin response, neuronal development and energy stasis. 4) Investigate whether orthologues of these enzymes in pathogenic bacteria are involved in prokaryotic O-GlcNAc and/or are virulence factors targetting ho st proteins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL;INFECTION;METABOLIC AND ENDOCRINE
Title: Glycosphingolipid catabolism and transfer in health, disease and immunity.
Funder: Wellcome Trust

Abstract: 1) To investigate the molecular mechanism of lipid binding and solubilisation by saposin molecules. 2) To reveal the molecular mechanism by which saposins A and C present substrate and activate GalC. 3) To fully investigate the consequences of known clinical mutations on GalC stability, activity, cellular location/trafficking and interaction with substrate, membranes and saposins. Can these parameters be affected in vitro and in vivo by inhibitor or chaperone binding? (In collaboration with Prof. Paul Luzio) 4) To reveal the molecular mechanism by which saposins load lipid antigens onto CD1d and CD1b molecules. To test the hypothesis that saposins mediate loading of specific myelin-related autoantigens, and determine whether autoreactive T cells or NKT cells exist in patients with Krabbe disease and Multiple Sclerosis (In collaboration with Prof. Timothy Cox).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Vitamin D receptor and sex hormone receptor chromatin immunopreciptation with exonuclease digestion and massively parallel DNA sequencing (ChIP-exo): associations with autoimmune disease and human evolution.
Funder: Wellcome Trust

Abstract: Human evolution has been characterised by migration from areas of high ultraviolet radiation (Africa) to areas of much lower ultraviolet radiation. Ultraviolet radiation is required to generate vitamin D. Autoimmune diseases, in which the body's immune system attacks itself, are associated with low levels of vitamin D and are increasing in frequency. We generated a map of where the protein that mediates the effect of vitamin D binds to the human genome, the blueprint for all genes that make up t he body, and showed that binding tends to occur at places associated with risk of autoimmune disease and considered important in human evolution. Autoimmune diseases affect women far more commonly than men. The reason for this is unknown but may be due to sex hormones, such as oestrogen, progesterone or testosterone, acting on immune cells within the body. We believe that by using new technology to generate an extremely accurate map of the places in the human genome where vitamin D and sex hormone proteins bind, we may be able to help uncover their roles in autoimmune disease and also shed light on certain aspects of human evolution. This may help with drug development to combat autoimmune diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Glasgow Clinical Research Facility: translating research into benefits for patients.
Funder: Wellcome Trust

Abstract: The University of Glasgow and NHS Greater Glasgow & Clyde together provide an outstanding environment for clinical research with a strong focus on translation from bench to bedside. This will be greatly enhanced by the opening of the new 900M South Glasgow Hospital, one of Europe's largest hospitals. We wish to develop a modern, multidisciplinary Clinical Research Facility (CRF) to focus on early stage clinical trials that will allow us to make significant advances in the treatment of chroni c diseases. The CRF will allow us to combine our strengths in inflammation (including rheumatoid diseases), cardiovascular medicine, cancer, neurology and child health to develop a world leading centre in chronic degenerative diseases. Our ability to link core patient datasets (including GP prescribing data) with health outcomes will underpin these approaches, as will the early inclusion of our statisticians and health economists in the design, planning and running of clinical trials. The juxt aposition of world class researchers with a population of chronic ill health will allow us to fully exploit the opportunities of the new South Glasgow Hospital to deliver benefit to patients locally, nationally and internationally. The CRF will also offer a rich training environment for clinical researchers and junior physicians.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL;INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS;CARDIOVASCULAR