NIHRDataInsights/HRCSData huggingface dataset:
Title: Interaction of systemic and central apolipoproteins in the pathogenesis and treatment of cerebral amyloid angiopathy
Funder: Alzheimer's Research UK

Abstract: Alzheimer’s disease (AD) affects more than 800,000 people in Britain and 35 million people worldwide, with numbers set to quadruple over the next 40 years. Accumulation of amyloid-β (Aβ) in the walls of cerebral blood vessels as cerebral amyloid angiopathy (CAA) damages their integrity and contributes to the observed dementia. Work from our lab suggests that CAA may develop in part due to impaired removal of Aβ from the brain along basement membranes in the walls of capillaries and arteries. For unknown reasons, people with high levels of plasma cholesterol and those who posses the apolipoprotein E4 (apoE) protein are at higher risk of developing AD and CAA. Apolipoproteins are necessary for cholesterol movement in the brain and periphery. In the brain, cholesterol is carried by apoE and in the blood, by apoA-I. Recently, it has been suggested that apoA-I might play a role in the development of CAA, through as-of-yet unidentified mechanisms In the current proposal, we will test the hypothesis that i) apoA-I influences Aβ accumulation by altering the efficiency of the perivascular environment to remove Aβ from the brain and ii) that altering levels of peripheral apoA-I will have beneficial effects on the development of CAA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neuronal network disruptions in a model of tauopathy
Funder: Alzheimer's Research UK

Abstract: Neurones in the brain are interconnected within complex networks, the electrical behaviour of which determines how we think and behave. In dementia sufferers these networks do not function correctly, contributing to the well-known memory problems associated with diseases like Alzheimer’s. The nature of the electrical activity in these networks is determined by multiple factors, including the strength of connection between nerve cells (synapses) and the intrinsic electrical properties of individual cells. In an initial study of a mouse which overproduces the tau protein (rTg4510 mice) we identified changes in the electrical and synaptic properties of cells in hippocampus and prefrontal cortex, brain regions crucial for learning and memory. These findings suggest these two brain regions communicate abnormally in diseases associated with excessive tau production. I propose to study the behaviour of these networks in normal and rTg4510 mice, using state-of-the-art recording devices which monitor the activity of individual cells and groups of cells. This will allow us to monitor the ‘brain waves’ (similar to EEG recordings) of these mice whilst they perform certain behavioural tasks which involve the hippocampus and prefrontal cortex. Understanding how neuronal networks malfunction in disease models will ultimately provide novel approaches for treating dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Measuring, Tracking and Disentangling the Impact of White Matter Disease in AD and Mixed Disease: A Longitudinal MRI and CSF Study
Funder: Alzheimer's Research UK

Abstract: People with Alzheimer’s disease (AD) often have evidence of vascular damage in their brains as well as Alzheimer’s pathology (amyloid and tau). Understanding the relative contributions of each pathology to disease progression is extremely important for numerous reasons. Trials of possible AD treatments are moving to earlier disease stages in order to prevent and halt, rather than treat disease, and even at these earlier stages vascular damage has an impact on progression. Those with more vascular damage may also respond differently to treatments and may have differing prognoses compared with those without such damage. This project will develop techniques to measure and assess the correlates of vascular damage using magnetic resonance imaging. We will make these techniques freely available for other centres to use. We will disentangle the relationships between AD pathology and vascular damage in terms of how each acts to increase disease progression and when each has the greatest influence. In this project we aim to gain understanding of these relationships which will provide better information for those designing clinical trials, for clinicians and also, most importantly, for patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identifying functional molecular pathways that underlie the earliest changes associated with Alzheimer’s Disease
Funder: Alzheimer's Research UK

Abstract: The already enormous economic and personal burden of Alzheimer’s disease will continue multiplying until we find interventions for the earliest stages of the disease. Current treatments come too late to tackle the irreversible changes that have already occurred when memory loss is first detected. I recently returned from Stanford University to set up a research programme using the cutting-edge techniques that I learnt there. I aim to identify the earliest molecular changes in brain cells that lead to this devastating condition. UCL provides an environment, unparalleled in Europe, for approaching this problem. UCL scientists are finding that communication between brain cells starts to fail long before we can detect the memory loss to which they eventually lead. The techniques that I bring to this major collaborative effort are essential to take the next step. By combining mouse genetics, genome-wide approaches, software-based predictions, molecular biology, electrical recordings and behavioural studies, and using the latest molecular and viral technologies, we can control the activity of specific genes, aiming to identify and correct the aberrations in intracellular pathways causing the identified early changes. These insights will be critical for finally identifying novel tools that delay or even prevent the progression of Alzheimer's disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: DREAM8.5 Alzheimer's Disease Big Data Challenge #1
Funder: Alzheimer's Research UK

Abstract: Open science computational Challenges such as the DREAM Challenges engage diverse communities of scientists to competitively solve a specific problem in biomedicine in a given time period. Challenges accelerate the time it takes to generate answers to computational research questions: in the 3-4 month open phase of a DREAM Challenge, 50 individuals or teams working simultaneously can do what would normally take 10 years for a single team to achieve working in isolation. The DREAM Challenges are run on Synapse, Sage Bionetworks’ open computational platform. Synapse serves not just as a data repository but also as a set of tools for conducting collaborative analysis, and as a seamless system for Challenge participants to share and document data, models, and analysis methods. The Global CEO Initiative on Alzheimer’s Disease (AD) is joining with Sage/DREAM to run a DREAM Challenge to identify the predictors of AD risk in pre-clinical populations. We see this first global Big Data Challenge on AD biomarkers, as part of global approach to identifying faster and more accurate predictive bio-markers that can be used by the scientific, industrial and regulatory communities. The AD Challenge will use multi-modal data from existing research cohorts with AD, and Challenge participants will be presented with specific questions and asked to build models that address those questions based on a test and adjacent datasets. These models will be scored using a validation dataset in order to identify a Challenge winner. This Challenge will utilize a subset of the ADNI data as the test dataset and the Rush Religious Orders Study (ROS) and Memory and Aging Project (MAP) cohorts as the validation set.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: NEUROLOGICAL
Title: High-throughput genotyping of rare variants identified through next-generation sequencing of Alzheimer's disease candidate genes
Funder: Alzheimer's Research UK

Abstract: Since 2006 the Nottingham Alzheimer's Research UK (ARUK) centre has developed a strong working relationship with the Mayo Clinic, Florida headed by Prof Steve Younkin (SY). The support of Alzheimer’s Research UK has been instrumental in this partnership; funding Kevin Morgan (KM) to visit the Mayo Clinic and Olivia Belbin (OB) to undertake a two year post-doctoral position. The strength of this collaboration is a 'bank' of over 10,000 patient samples (one of the largest in the world) – an ideal resource for large genetic association studies; as exemplified by our joint publications on the ‘top’ 25 AD genes to date. With OB having completed her position in 2010, there is an opportunity for myself (CM) to continue this relationship. We plan to utilise the shared resource to perform high-throughput replication studies of common and rare variants currently being discovered through our targeted resequencing of Alzheimer's disease candidate genes. As 6-months funding has already been committed by SY at the Mayo Clinic, we are applying for 2.5 years further funding; 6-months matched funding for one year at the Mayo Clinic, which will be preceded by 6-months preparation in the UK and proceeded by 1.5 years back in the KM lab.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Whole exome sequencing in familial Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: Our knowledge of Alzheimer’s disease (AD) genetics has greatly improved in the past few years. Mutations in three genes (APP, PSEN1 and PSEN2) are known to be the genetic cause of disease in several families and AD patients. Additionally, several genetic risk factors have also been associated with AD. Nonetheless, many families afflicted with Alzheimer’s disease do not have a mutation in these genes. Because the disease is present in several members of the same family, a genetic cause is suspected. In this project we want to study families with no mutations in the known AD genes in order to identify new genes and genetic alterations in the basis of the disease. To do this we intend to sequence all the genes present in the genomes of several family members and compare the results for each stretch of DNA between affected and unaffected subjects. To increase the power in our analyses we willl study each family individually and combine families with similar features. Results from this study will not only allow a better family counseling and clinical management, but will also be important in finding new proteins, pathways and, ultimately, new therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Exploring Ca2+ signalling in a Friedreich’s ataxia mouse model
Funder: Ataxia UK

Abstract: Friedreich’s ataxia (FRDA) is a hereditary neurodegenerative disorder caused by an abnormal repetition of a 3-base pair sequence (GAA) in the frataxin gene (FXN), which reduces the expression of frataxin, a mitochondrial protein. Patients carrying this mutation develop ataxia variably associated to hypertrophic cardiomyopathy and diabetes. Frataxin acts as an iron detoxifier, as well as an iron chaperone in iron-sulphur clusters and heme biosynthesis. Frataxin deficiency causes iron accumulation, reactive oxygen species (ROS) generation and malfunction of the metabolic pathways. Defects in mitochondrial metabolism and oxidative stress may cause calcium deregulation. Studies on oxidative stress found that ROS generation is linked with calcium release from the intracellular stores in FRDA patient fibroblasts. Therefore we aim to study the role of calcium and its physiology in a FRDA mouse model (YG8R), by examining mitochondrial and cytosolic Ca2+ of different cell types. In the present project, in particular, we would explore the role of Ca2+ in cardiomyocytes, as it is known that iron accumulation causes Ca2+ deregulation at the level of the L-type Ca2+ channels (LTCC), which are crucial for the Ca2+ homeostasis. The aim of this study is to seek new therapeutic targets for the restless battle against FRDA.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Visual dissection of GAA-mediated mechanisms of FRDA repression and identification of novel candidate factors involved in frataxin function
Funder: Ataxia UK

Abstract: Friedreich’s ataxia (FRDA) is a disease caused by low levels of a protein called frataxin. What is known about the cause of FRDA is that the low levels of frataxin are due to a mutation in the gene (FXN) coding for frataxin, in particular a 3-base pair sequence (GAA) repeated up to 1700 times in the mutated FXN gene. We still do not know the exact mechanism by which the GAA mutation is causing a reduction in frataxin levels. With our research, we are developing tools to understand more about the mechanism responsible for the low frataxin levels as well as identifying promising therapies for this disease. Recently, we have developed cells that carry the same GAA mutation which causes the switching off of the FXN gene in FRDA. We have used these cells to test a novel group of molecules and we have identified a promising new drug that increases frataxin levels in blood cells from FRDA patients. To understand more about the mechanism by which GAA repeats affect frataxin levels, we have generated a cell model which allows us to study in real time and in living cells the direct effect of the GAA mutation on RNA synthesis, the first step involved in the cellular production of the protein frataxin, and observe the way the GAA mutation affects this process. We demonstrate here that the mutation affects the RNA synthesis step in our cell model and we will dissect this further in the experiments proposed. Furthermore, we also demonstrate that the GAA mutation changes the position of the FXN gene in the nucleus, which could be linked to the lower levels of FXN RNA synthesis. Here we request a six-month extension to carry out the experiments required to complete this study and publish our novel results.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Beta-band EMG-EMG coherence: a novel, painless and simple screening test for the onset of corticospinal tract disease/dorsal root ganglionopathy in Friedreich’s ataxia
Funder: Ataxia UK

Abstract: Project Objectives The main objectives of this project are to demonstrate that: 1. By combining multi-modal tests incorporating clinical assessments, MRI, electrodiagnostic testing and functional cellular/molecular assays into a screening algorithm it is possible to track the progression of disease in Friedreich’s ataxia (FRDA) accurately; 2. By including the measurement of beta-band intermuscular coherence (BIMC), multi-modal screening will be more efficient and more effective. An important secondary objective of this project is to complete development of a handheld electronic device capable of measuring BIMC in any setting, including primary care clinics and the home. Specific aims A. To develop a painless, inexpensive and easy-to-use portable electro-diagnostic screening test of subclinical dorsal root ganglionopathy (DRGopathy), dorsal column degeneration and corticospinal tract degeneration in Friedreich’s Ataxia (FRDA). B. To compare the performance of this electrodiagnostic marker against that of emerging functional in vitro cellular and molecular assays of disease activity in FRDA. C. To assess what happens to electrophysiological and molecular/cellular measures with increasing duration of disease in a prospective study of FRDA patients in the North of England and thus establish the basis for a future multi-centre longitudinal trial of these tests as markers of progression (or surrogate outcome measure) for future therapeutic trials.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Investigating the mechanisms of long-range epigenetic gene regulation (LREGR) at the Friedreich's ataxia (FRDA) locus
Funder: Ataxia UK

Abstract: GAA repeat expansions in the FXN gene causing Friedreich's ataxia (FRDA) have recently been suggested to induce multiple coordinated changes in epigenetic gene expression far up- and/or downstream of the FXN locus, a process termed long range epigenetic gene regulation (LREGR). Detailed investigation of these novel aspects of FRDA epigenetics represents a promising approach to better understand and treat FRDA disease. The aim of the project is to analyze long-range gene expression changes caused by GAA expansions at the FRDA locus and to gain insights into the underlying mechanisms at relevant loci, including the PIP5K1B locus. Using various cells from FRDA patients (primary fibroblasts and lymphoblastoid cell lines), and focusing on a genomic region of nearly 900 kb encompassing 5 genes of interest up- and downstream of the GAA expansion (5'- PGM5 - PIP5K1B - PRKACG - FXN - TJP2 -3'), we will combine methods for studying the relationships between gene expression changes, gene transcription status and specific epigenetic modifications. This work is expected to lead to the identification of additional target genes and novel epigenetic modifiers relevant to the FRDA phenotype, which will contribute to advance our understanding of FRDA physiopathology and ultimately to initiate novel therapeutic strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Engineering human neural networks
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The creation of an in-vitro model of the human brain (iBrain) will involve a 'bottom-up' approach by engineering and assembly of 'elements' (synapses), 'units' (neural networks) and 'domains' (structured compartments). The proposed project, as stage I of iBrain, focuses on the formation of a biological neural network (bNN), capable of learning, initially from NT2.D1 cultures and then human stem cells. Specifically we will differentiate human stem and NT2.D1 cells into functional neurons, selecting specific scaffolds and optimising culture conditions to direct their growth into 3-D architectures, so facilitating synaptic connection formation. Such screening and optimisation studies will involve multiple parallel perfused microbioreactors. The NT2.D1s will be transfected with channelrhodopsin 2 capability, facilitating axon stimulation through digital light processing. The bNN's will be formed using guided cell self assembly and tissue engineering and will involve a blue-light stimulated input layer, (473 nm), followed by an output layer (monitored with Ca2+ imaging). A middle layer will be created using collagen-based constructs. Functional measurement through electrophysiological and optogenetic approaches will monitor action potentials in individual neurons, and synaptic currents will be detected with grid electrodes to observe spiking at the output layer, and 2-photon microscopy will record Ca2+ transients as a measure of net activity. 'Training' of bNNs in pattern recognition by inducing targeted synaptic plasticity will be by repetitive stimulation, so showing ability to distinguish between stimuli. Once self-organized, the bNN's will respond to inputs (supervised learning). Functional bNNs will be monitored in neural plasticity during aging and degeneration. Ultimately, we will create 'functional 'domains', i.e., a large cluster of inter-connected multi-compartment clusters of bNNs, which is effectively artificial human brain tissue.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: CARMEN e-Science Portal
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The study of the brain is a priority area for biological research. Neurophysiological techniques (intra/extracellular recording, multielectrode arrays, EEG etc) are widely used to understand how individual neurons and networks contribute to brain activity. The mass of data generated requires detailed analysis to extract important information about regulatory mechanisms and patterns which contribute to overall activity. CARMEN is an e-science web portal specifically developed to enable researchers to share time-series data and analysis services within a virtual working environment. Since 2006 a collaboration across 11 UK universities has developed the first version of this resource. Using web access, data files can be uploaded to the platform and metadata added via a structured schema. Community-derived services are then used for analysis, with a common internal file format facilitating interoperability of different data and service formats. A security layer allows users to initially work in private groups, but once published data can be made public. Thus, CARMEN both curates experimental data and provides a public resource for secondary analysis. This reuse of data adds significantly to their value, particularly for complex or rare experimental contexts. The current project will maintain and develop the CARMEN resource for a further 4 years, particularly supporting transition to wider engagement. The main objectives include: significant promotional activity; technical workshops and 'help desk' support for new users; further versioning of the portal; technical development to support EEG recording and time-series data extracted from optical methods; and, through close links with the INCF, interfacing CARMEN with other bioinformatics resources to create a federated repository. Thus, CARMEN will leverage advances in cloud computing to deliver a unique resource to facilitate collaboration and data sharing, with significant impact on understanding of neural systems


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL