NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the structure and functional mechanisms of retinoschism in the mmammalian retina.
Funder: Wellcome Trust

Abstract: The laminar structure of the retina is essential for normal neural processing and the retinal-specific octameric protein, Retinoschisin has an essential role in its maintenance. The structure and function of Retinoschisin remains elusive, however, I determined the Cryo-electron microscopy structure in a rotation project, unveiling a novel 'octamer-dimer' structure. Interrogation of this may yield further insight towards the function of Retinoschisin. The proposed project contains three principal aims: (i) further high-resolution structural studies of multiple oligomeric states and specific domains within both wild-type and disease-associated mutant protein will provide novel structural information; (ii) the significance of the 'Octamer-Dimer' will be investigated to determine its importance in retinal adhesion, potentially suggesting a novel mechanism for the maintenance of retinal architecture; (iii) studying the binding and structure of Retinoschisin in complex with known interacting partners (Na/K ATPase-SARM1 complex and the L-VGCC potassiumion channel) will provide further mechanistic detail. Identification of potential new binding partners will also be carried out to provide a fuller understanding of Retinoschisin function. This project aims to provide novel structural and functional information to elucidate the currently uncharacterised mechanism by which Retinoschisin is able to maintain the architecture and neural processing in the mammalian retina.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;EYE
Title: Defining signalling pathways that control neurovascular interactions in the brain and retina.
Funder: Wellcome Trust

Abstract: The brain and retina contain millions of nerve cells that transmit messages from one part of the body to another and are nourished by blood vessels. Blood vessels additionally control brain and retinal development and may even promote the formation of new nerve cells in adults. The loss of communication and interaction between nerve cells and blood vessels causes brain and retinal disease. My team will investigate how nerve cells shape blood vessel networks to optimise their own function, how bl ood vessels stimulate the production of new neurons, and how new vessel growth may be stimulated in the diseased brain and retina without perturbing the function of healthy nerve cells. Acquiring such fundamental knowledge about nerve and blood vessel interactions will bring forward the development of effective therapies to repair nervous tissue damaged by ageing, injury or chronic disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;EYE;CARDIOVASCULAR
Title: Discriminant Function Analysis for Longitudinal Data: Applications in Medical Research (DiALog)
Funder: Medical Research Council

Abstract: Identifying the correct diagnosis as early as possible, especially before the patient presents clear structural and/or functional changes, is key for a successful treatment. For example, delays in the treatment of patients with suspected encephalitis can have a devastating impact, including severe cognitive disability. Hence, it is not surprising that in most medical disciplines research focuses on identifying biomarkers and risk factors, some of them measured over time, to correctly predict patient outcomes. We propose to develop a novel statistical methodology that allows us to identify patients at higher risk of developing a particular disease or condition sooner than is currently achieved, with subsequent benefits for patients, clinicians and for health care system costs. Discriminant function analysis can be used to make predictions of the group to which a patient most likely belongs (e.g., groups defined by high/low risk of developing diabetic retinopathy within a year). The use of longitudinally observed data can be particularly powerful in discriminant analysis. In longitudinal data analysis, responses are recorded at different time points and/or different locations, adding a longitudinal dimension to the data set. A promising approach to discrimination using longitudinal data for clinical applications is via extension of linear mixed models. We aim to develop a novel time-dependent approach for discriminant analysis that (a) depends directly on both the individual baseline covariate information and the longitudinal data to achieve a more precise classification, (b) allows us to detect the earliest time point at which successful classification can be achieved (with a predefined error), and (c) can be applied to classify individuals into two or more groups, with unequal variance-covariance matrices among groups and incorporation of costs. Our objectives are divided into 3 main parts: development, implementation and clinical applications.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: NEUROLOGICAL;EYE;METABOLIC AND ENDOCRINE
Title: Expression and purification of C21orf2 protein (implicated in ALS) for structural and functional studies
Funder: MND Association

Abstract: C21orf2, a leucine rich repeat (LRR) protein has recently been reported as an important risk factor for ALS and have identified several mutations relevant to the aetiology of ALS. The biological function of C21orf2 is not particularly well understood. It has been reported that C21orf2 interacts with NEK1, another ALS risk factor and like NEK1, is implicated in DNA repair mechanisms. Gaining insights into the specific role played by C21orf2 by means of structural studies is essential for an improved understanding of protein function at the molecular level. In the longer term, this will provide the best possible platform to design potential therapeutics and develop treatment strategies to target the disease in future. This funding will support an undergraduate student to undertake a university-based research project instead of a 'year in industry'. The aim is to express and purify large quantities of human C21orf2 protein (both large and shorter isoforms) using bacterial, mammalian and yeast expression systems for structure-function studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Title: Advanced Micro-optofluidic Portable Sensing (AMPS) Technology for Timely Point-of-Care Diagnostics
Funder: Royal Academy of Engineering

Abstract: To realise the next-generation tools for the point-of-care (PoC) diagnostics, our work focuses on developing a highly-innovative, reliable, diagnostic technology for rapid detection of biomarkers at trace-level concentrations from biofluids, urgently needed in many clinical areas to accelerate the successful early-diagnosis of major diseases. Our portable AMPS technology is based on controllable electrohydrodynamic (EHD) sub-microstructures engineered for advanced SERS detection. AMPS prototype is being developed to combine sensitive, reproducible and molecule-specific EHD-SERS lab-on-a-chip with miniaturised optofluidic platforms to enable real-time diagnostics. This technology will be of particular value in scenarios where PoC assessment of patients is vital and the damage becomes more significant with time. It will be validated for the detection of biomarkers indicative of traumatic brain-injury, a leading cause of death and neurological disability worldwide with millions of people sustaining and living with its long-term effects.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Title: Holographic Light Shaping for Reverse Engineering Neural Circuit Learning
Funder: Royal Academy of Engineering

Abstract: Underlying our senses, perceptions, thoughts and actions are 100 billion neuronscommunicating through electrical and chemical signals. One of the most important toolsfor learning how the brain learns, processes and stores memories is to stimulate someneurons and observe how others react. Over the past hundred years, this wasaccomplished with electrical stimulation to shock one neuron or a whole brain area.However, networks of neurons wire together in complex patterns that cannot beemulated with electrode stimulation. Over the past 10 years, geneticists have workedout how to render neurons sensitive to light. Shining light onto the neurons can eitherexcite or silence them. As a RAEng Research Fellow, I have been prototyping aspecialized microscope capable of shaping light onto the brain to activate neurons inpatterns that can mimic that of naturally occurring activity. Once fully developed, thismicroscope will be distributed to neuroscientists worldwide, providing a powerful newtool for discerning how neuronal communication gives rise to brain function anddysfunction, learning and memory.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Title: Characterizing the brain’s spatio-temporal dynamics by integrating EEG and FMRI
Funder: Royal Academy of Engineering

Abstract: My research focuses on integrating simultaneous measurements ofelectroencephalography (EEG) and functional magnetic resonance imaging (fMRI), togenerate images of brain activity that are better than either technique is able to producealone. Recently, I have been addressing some challenges of using these techniquessimultaneously, making my ultra-fast fMRI scanning methods compatible with EEGmonitoring, laying the groundwork for the integration. Once this is complete, I can beginexperiments that, for example, will isolate epileptic foci using EEG to identify epilepticspikes, and fMRI to identify the location of these spikes with higher resolution thancurrent methods allow.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Title: Molecular mechanisms driving the formation of the neuronal microtubule cytoskeleton
Funder: Wellcome Trust

Abstract: Neurons are highly polarized cells with two structurally and functionally distinct projections emanating from their cell bodies — the axon and the dendrite. During neuronal development the radial microtubule array in a neuronal precursor reshapes, acquiring uniform polarity in axons and mixed polarity in dendrites. Distinct microtubule-associated proteins regulate microtubule function in neurons, and mutations in these proteins are linked to human neurodevelopmental disorders. However, the molecular mechanisms that facilitate microtubule remodeling in a developing neuron are poorly understood. My research aims to gain a detailed mechanistic understanding about how neuronal cells assemble and maintain their complex microtubule architecture. Recently, I discovered that components of the kinetochore, the ancient and conserved microtubule-coupling machinery that segregates chromosomes, are redeployed during neurogenesis. Starting from this novel insight, I will determine how kinetochore and non-kinetochore factors regulate microtubule remodeling during neuronal development in C. elegans embryos. In parallel, I will use in vitro mammalian neuronal differentiation systems to extend functional analysis of neuronal microtubule regulators. The proposed research has the potential to provide detailed insight into how the microtubule cytoskeleton is reorganized to build a complex differentiated cell type, advance our understanding of neuronal morphogenesis, and explain the basis for microtubule-related neurodevelopmental disorders.

Lay abstract: Inside cells, microtubule polymers are parts of a vast network called the cytoskeleton. This network, although highly dynamic, can be specifically arranged to perform different cellular functions. During cell division, the cytoskeleton forms the mitotic spindle, a compact force-generating structure that separates the duplicated DNA. In contrast, during brain development the organization is quite different, with extensive parallel structures forming inside the neurons. How the cytoskeleton can undergo such dramatic shape changes to perform specialized tasks is poorly understood. Many microtubule-associated proteins (MAPs), including stabilizers and destabilizers, operate to tune the cytoskeleton. I found that some MAPs of the mitotic spindle are also active during neurogenesis. Also, mutations in them are linked to human neurodevelopmental disorders. I will combine genetic tools with light microscopy to understand how these proteins function and how their overall activity contributes to shaping the neuronal cytoskeleton in the model organism C. elegans and human cells.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Title: Investigating how cell surface mechanics gates intracellular signalling to instruct cell fate choice
Funder: Wellcome Trust

Abstract: In order to perform their function (differentiation or self-renewal), stem cells need to receive a signal. Historically, the focus was put on the importance of soluble factor signals, but it is nowadays widely appreciated that the mechanical environment of stem cells plays a role in their function and affects soluble factor signalling. This is for example illustrated in oligodendrocyte progenitor cells (OPCs). With ageing, due to alterations in stiffness of the extracellular matrix (ECM) in the brain, OPCs lose their function, becoming unable to give rise to oligodendrocytes, a cell type which supports neurons. Using human pluripotent stem cells (hPSCs) and OPCs as systems, I will investigate the mechanism which underlies the effect that various properties of the mechanical environment (stiffness, stability) have on interpretation of soluble factor signalling (intracellular signalling) in stem cells and on their function. In response to different properties of the mechanical environment, I will monitor changes in membrane tension, receptors binding ECM and signalling platforms clustering soluble factor receptors. Understanding of how cell surface mechanics gates intracellular signalling in a basic model such as the hPSCs can further be applied to OPCs to shed light on how and why OPCs lose function as they age.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Title: The feasibility and practicality of dementia risk reduction in the older population: A pilot trial
Funder: Alzheimer's Research UK

Abstract: Thirty percent of Alzheimer’s cases have been linked to lifestyle behaviours such as smoking and physical inactivity. Currently, much prevention focuses on the younger-old (<75) rather than those who are at highest immediate risk of developing dementia. Internet counselling, targeting lifestyle behaviours, is being developed as a possible way to reduce or delay our risk of developing dementia. We propose to pilot an internet counselling intervention in an existing cohort study (Cognitive Function and Ageing Study (CFAS)); to investigate feasibility and acceptability to UK populations and whether the outcome measures are suitable for a full-scale trial. Of 72 recruited participants per site (Cambridgeshire, Nottingham, Newcastle); half will receive internet counselling with coach support, the other half will receive a static website. Information will be collected about participant’s memory, thinking skills and risks of heart and other health problems at the start and end of the study (12 weeks apart). A further group, who will not receive interventions will continue to be part of the observational study. This allows us to test whether the trials recruitment itself changes behaviour and if we can, or cannot, recommend a larger internet based trial for reducing dementia risk in older people in the UK.

Lay abstract: Thirty percent of Alzheimer’s cases have been linked to lifestyle behaviours such as smoking and physical inactivity. Currently, much prevention focuses on the younger-old (<75) rather than those who are at highest immediate risk of developing dementia. Internet counselling, targeting lifestyle behaviours, is being developed as a possible way to reduce or delay our risk of developing dementia. We propose to pilot an internet counselling intervention in an existing cohort study (Cognitive Function and Ageing Study (CFAS)); to investigate feasibility and acceptability to UK populations and whether the outcome measures are suitable for a full-scale trial. Of 72 recruited participants per site (Cambridgeshire, Nottingham, Newcastle); half will receive internet counselling with coach support, the other half will receive a static website. Information will be collected about participant’s memory, thinking skills and risks of heart and other health problems at the start and end of the study (12 weeks apart). A further group, who will not receive interventions will continue to be part of the observational study. This allows us to test whether the trials recruitment itself changes behaviour and if we can, or cannot, recommend a larger internet based trial for reducing dementia risk in older people in the UK.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Title: Marie Curie Chair in Palliative and End of Life Care, UCL
Funder: Marie Curie

Abstract: This grant was awarded to UCL in order to establish a Chair in Palliative and End-of- life care, and to lead the Marie Curie Palliative Care Research Department. Prof Paddy Stone was appointed to this post in April 2014. The grant was awarded for 1O years and successfully passed a planned interim review after 5 years. The grant was not awarded to undertake a specific plan of work. According to the job description, the post holder is responsible for, "Leading a world-class programme of research and providing leadership in research and teaching in Palliative and End of Life Care in MCPCRD, the Faculty of Brain Sciences and across UCL". No specific milestones or objectives were set for this post. This was because the award was given to a person rather than to a specific project. The flexibility and freedom to respond to the changing research environment that this has afforded has been the key to the success of the post. Prof Stone leads a department which undertakes research into ?End of life care? (including studies on prognostication, sedation and symptom control) and palliative care in ?seldom-heard? groups (including the palliative care needs of people with dementia, the homeless and patients with advanced liver disease).

Lay abstract: This grant was given to establish a new post of "Professor in palliative and end-of-life care" at UCL. Marie Curie awarded funding for 1O years. After the post had been openly advertised, and following a competitive interview process, Prof Paddy Stone was appointed to the post and took up his position in April 2014. According to the job description, the post holder is responsible for, "Leading a world-class programme of research and providing leadership in research and teaching in Palliative and End of Life Care in MCPCRD, the Faculty of Brain Sciences and across UCL". Prof Stone leads a department which undertakes research into ?End of life care? (including studies on predicting survival in patients with advanced disease, the use of sedatives at the end of life and the best way to manage specific symptoms such as fatigue) and palliative care in ?seldom-heard? groups (including the palliative care needs of people with dementia, the homeless and patients with advanced liver disease).

Research activity codes: 7.2 END OF LIFE CARE
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Title: Modelling the molecular pathogenesis of triple A syndrome (AAAS) with iPSC-derived neurons and adrenocortical cells.
Funder: Medical Research Council

Abstract: Triple A syndrome (AAAS), a rare disorder, presents with tissue-specific degeneration. Encoded by the AAAS gene, ALADIN is a nuclear pore complex (NPC) protein necessary for nuclear import of DNA protective molecules and is important for redox homeostasis. ALADIN's role is not fully characterised: its discovery at the centrosome and the endoplasmic reticulum suggests a role outside the NPC. Mitochondrial dysfunction may be implicated by disruption of mitochondrial steroidogenic enzymes, enlarged mitochondrial mass and increased mitochondrial superoxide species. My preliminary data shows ALADIN localisation to mitochondria in SHSY5Y cells. Investigation of AAAS is marred by suboptimal models. In collaboration, I have generated novel induced pluripotent stem cell (iPSC) models of disease using CRISPR-Cas9 gene-editing: 1) Homozygous knock out (AAAS-KO) and 2) Homozygous hotspot mutation (AAAS-mutant). The unedited iPSC will serve as an isogenic control. Aim: To differentiate the AAAS-iPSC and controls towards adrenal-like and neuronal phenotypes, for use in: 1. OS profiling of AAAS, including mitochondrial phenotyping. 2. Identification of gene expression in AAAS, signposting ALADIN's non-canonical functions. Method Differentiation: Through established in-house pipelines. OS profiling: Susceptibility to OS/bioenergetic response in the AAAS-mutant, AAAS-KO and control cells will be assessed by XFe96 extracellular flux analyser. If mitochondrial dysfunction is confirmed, mitochondrial phenotyping will ensue. RNA Seq: AAAS-KO neurons (clones, n=10) and controls (clones, n=10) will be sent for RNA seq. Bioinformatics will be performed with in-house expertise. Recapitulation in adrenal cells will identify pathways common to both tissues. Functional experiments will target genes/pathways of interest to reverse the AAAS phenotype. Impact: Insight into the pathogenesis of AAAS has therapeutic development potential for AAAS/degenerative diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Investigating Epstein-Barr virus and MS
Funder: Multiple Sclerosis Society

Abstract: What's the project about?_x000D_ _x000D_ MS is thought to be an autoimmune condition, where the bodyâ€™s own immune system mistakenly attacks healthy tissue. One possible explanation of this â€˜autoimmuneâ€™ behaviour is that a virus might cause a strong immune response and some of that response recognises not only the virus but also, by chance, normal parts of the central nervous system, like myelin._x000D_ _x000D_ There is evidence to suggest a possible role in MS for a virus called Epstein-Barr virus (EBV). EBV is a common virus that most people acquire in early life and is then carried for life usually with no harmful effects. This project led by Dr Jill Brooks at the University of Birmingham aims to determine whether or not the immune response to EBV in people with MS really does contain cells that cause this autoimmune response and could damage myelin. _x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ By investigating the possible causes of MS the results of this project could lead to new ways of diagnosing or treating MS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;INFECTION