NIHRDataInsights/HRCSData huggingface dataset:
Title: DRI-Clinical: biological resources and clinical collaboration
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. The capacity to carry out experimental medicine and find therapies is critically dependent on understanding disease in the human –there is no substitute for this. Clinical cohorts and material can contribute to the aims of a DRI from defining genetic effects (e.g. biochemical, cellular and clinical manifestations) through to biomarker and assay validation and on to first-into-human therapeutic studies. Genetic disorders permit the study of premanifest mutation carriers with the opportunity to study the onset (and potentially intervene to alter the course) of molecular pathology and subsequent symptoms. Premanifest cohorts provide the substrate for determining the ordering of pathological effects and what may modify those cascades; they offer the opportunity to test and validate “proximity” markers, i.e. measures that predict imminent functional decline. In addition to their translational potential, such cohorts constitute a unique resource for studying disease neurobiology in pure form and a bridge from transgenic to human studies. Studies across different diseases e.g. (f)AD and (f)FTD offer the prospect of identifying common mechanisms of neurodegeneration that extend beyond particular diseases. Whilst the study of genetic cohorts provides a scientifically tractable focus, clinical and molecular heterogeneity means that it is also essential to study sporadic disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Understanding Alzheimer’s disease-related genetic variability
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. The last decade has seen the development of new genotyping and sequencing platforms. The application of these new genomic technologies to the study of Alzheimer’s disease, other dementias and neurological diseases in general, led to the identification of new genes and biological pathways associated with these disorders.The genetic study of multigenerational families where disease segregates led to the identification of diseasecausing mutations in several genes, which provided us with the first clues into the pathobiological events involved in these diseases. More recently, genome-wide association studies (GWAS) have identified several loci that modulate risk for disease, albeit individually, with small effect sizes. This is true for nearly all major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Frontotemporal dementia (FTD) and Dementia with Lewy bodies (DLB). The following step-change was the introduction of next-generation sequencing, which allowed us to identify variants that are rarer in the general population, but that have larger effect sizes. TREM2 in AD is a prime example of this, although other genes, such as SORL1 and ABCA7 have also been further characterised through the application of this technology. One of the main outcomes of these recent approaches was the prediction of the involvement of specific biological pathways in these individual disease entities. In AD, the immune response, cholesterol metabolism, regulation of endocytosis and proteasome-ubiquitin activity have been implicated in disease pathogenesis, while in Parkinson’s disease, GWAS results indicated the involvement of the lysosomal pathway and mitophagy. The involvement of these pathways is, however, very broadly defined: genes encoding proteins that are part of these pathways either contain rare mutations or common variants with small effects more frequently in disease individuals than in healthy controls. This involvement is also based in current knowledge, as only the functions already known to be associated with these proteins can be associated with disease. What is now required is the next step-change: understanding the mechanistic effects of the genetic variability that has been shown to be involved in disease


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Fluid biomarkers for neurodegenerative diseases
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Amyloid β (A), the key component of extracellular senile plaques in Alzheimer’s disease (AD) brains, is produced from amyloid precursor protein (APP) by proteolytic processing via the -site APP-cleaving enzyme 1 (BACE1) and the -secretase complex in all human beings. According to the Aβ cascade hypothesis, AD is caused by abnormal accumulation of Aβ in the brain [1]. This process is thought to induce, by unknown means, hyperphosphorylation of the axonal protein tau, formation of intra-neuronal tau inclusions (neurofibrillary tangles) and frank neurodegeneration. The ultimate proof of the Aβ cascade hypothesis would be if an Aβ-targeting drug successfully slows down AD in a clinical trial. However, this has not yet happened. Instead, the hypothesis has been challenged by negative results in several phase III clinical trials aimed at inhibiting Aβ production (secretase inhibitors), or increasing its clearance from the brain (anti-Aβ immunotherapy). I argue that recent trial failures were not adequate tests of the Aβ cascade hypothesis: a major limitation of our understanding and a key barrier to progress is that we do not know whether dosages were high enough (likely not) to engage their targets; we do not know (in vivo in humans) what the effects of whatever (possibly limited) target engagement were on the multiple pathological factors in AD, nor do we know what the downstream effects on intermediates between molecular pathology and clinical decline were – the potential to examine brain tissue histopathologically during or immediately after such trials is extremely limited – and therefore improved biomarkers and improved interpretation of biomarkers are critical. Furthermore, trials in pre-clinical disease stages, e.g., such that are planned in the Dominantly Inherited Alzheimer Network (DIAN), will at least be needed to address the Aβ cascade hypothesis – these trials bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not clinically affected. The negative trial outcomes have also highlighted the need for more translational research on disease models to study AD pathogenesis, screen for and evaluate new drug candidates and establish pharmacodynamic biomarkers to verify target engagement and translate model findings to valid readouts in clinical trials. Along similar lines, we need new biomarker tools to study the pathophysiological relevance of and cellular responses to a number of non-A pathologies that are common in AD and highly relevant to several other neurodegenerative diseases, namely tau, -synuclein and TDP-43.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Deciphering the cellular phase of AD using Single Cell Genomics
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Dr. Carlo Sala Frigerio will move together with the director to the UCL hub and take the full responsibility of the single cell core of the institute. His aim is to contribute to the full understanding of the cellular phase of Alzheimer’s disease (AD) and to identify critical pathways and cell biological responses that might help to develop novel therapeutic approaches for AD. He has extensive experience in genetics, biochemistry, molecular and cellular biology and genomics, as demonstrated by his publications. Since two years he has set up the single cell biology core in the laboratory of Bart De Strooper and several publications are in preparation. The move to UCL will allow to switch the focus of research towards human brain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Restoring axonal transport deficits as a therapeutic strategy for neurodegenerative diseases
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. The precise cause of neuronal death found in many neurodegenerative diseases, such as Alzheimer’s disease (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is poorly understood. Key consequences of this gap in knowledge are that few and largely ineffective symptomatic treatments for these pathologies are on offer in the clinic, and that no disease modifying therapies are presently available. These considerations and the failure of several high-profile clinical trials make innovative drug discovery targeting neurodegenerative diseases an urgent societal priority, and highlight the need for a step change in the strategies to fight these pathologies, moving from classical biochemical screens to pathway analysis approaches. We have been investigating ALS as a disease paradigm to identify new common targets for pharmacological intervention in these devastating diseases. Different mechanisms have been linked to the pathogenesis of ALS, including proteostasis impairment, mitochondrial dysfunction, alterations in RNA dynamics, deregulation of the NFKB pathway and deficits in axonal transport (1, 2). However, a major shortcoming of these studies is the inability to distinguish between mechanisms that determine ALS pathogenesis, and cellular and molecular processes that are instead a consequence of this pathology, a consideration that extends to AD and other neurodegenerative conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Frontotemporal dementia disease mechanisms
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. C9orf72 repeat expansions are a common cause of neurodegenerative disease Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders for which no effective therapies exist. Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of both FTD and ALS, making them one of the most frequent single gene causes of neurodegeneration identified to date. Whilst < 33 GGGGCC repeats occur in the healthy general population, with just 2 repeats being the most common, C9orf72 FTD/ALS (C9FTD/ALS) cases carry 500- 4400 repeats. C9orf72 repeat expansions can cause neurodegeneration through arginine-rich proteins The expanded repeats have been hypothesised to cause disease by three non-mutually exclusive mechanisms: i) reduced expression of C9orf72, ii) toxic sense and antisense repeat RNA species that sequester key RNA binding proteins or iii) toxic dipeptide repeat (DPR) proteins, generated by repeat associated non-ATG translation. The GGGGCC repeat can be translated in all sense and antisense frames, two of which code for the same DPR, resulting in five DPR proteins: poly-glycine-arginine (GR), polyproline- arginine (PR), poly-glycine-alanine (GA), poly-glycine-proline (GP), and poly-proline-alanine (PA). We have made several key contributions to understanding C9FTD/ALS 1-4 and have provided evidence that loss of function is not the primary cause of disease 3. In addition, complete knockout of C9orf72 in mice does not lead to neurodegeneration, but rather to immune defects 5, indicating that loss of function may modulate the disease process, but is not the key driver of disease. We have therefore focussed on gain of function mechanisms. We recently reported the development of tools that


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Humanised models: the role of Wnt signalling & axonal transport in neurodegenerative disease
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. This application proposes two aligned projects: (i) Wnt signalling pathway in synapse maintenance, plasticity and protection. (ii) Axonal transport in neurodegenerative disease. Both projects are directly linked to ongoing projects within the Alzheimer’s Research UK Drug Discovery Institute at UCL (DDI). They fulfil two key strategic goals which align with both the DRI and the DDI remits: to further understand two key areas of neurodegenerative biology, and to identify new drug targets. An additional important focus is the use of human model systems, which is currently a critical gap; this is key in the context of developing therapeutics (“humanising drug discovery”). (i) Wnt signalling pathway in synapse


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mechanism of the DNA Bates
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Huntington’s disease (HD) is caused by the expansion of a CAG repeat tract in exon 1 of the HTT gene, and early pathogenic events that are proximal to the mutation have recently been identified. Somatic expansion of the CAG repeat in specific brain regions and peripheral tissues occurs with disease progression in both HD patients and mouse models. It has been known for many years that ablation of specific mismatch repair proteins completely ablates somatic CAG repeat expansion, and the identification of these same mismatch repeat genes as genetic modifiers of HD, by the Tabrizi lab and others, has brought DNA repair and somatic expansion sharply into focus. At the same time, we have found that the incomplete splicing of the huntingtin gene (HTT) generates a small transcript (Httexon1) encoding an exon 1 HTT protein, and that the extent to which this occurs is CAG repeat length dependent. Therefore, we have identified a mechanism by which genetic modifiers of HD are linked directly to the production of what is known to be a highly pathogenic protein. We have optimized our method for measuring CAG repeat expansions in mouse tissue, are generating a panel of quantitative qPCR assays to measure all HTT transcripts and have established a multiplex quantigene assay that can be used to measure relative HTT expression levels directly in tissue lysates. We have established a TR-FRET assay that measures the levels of the exon 1 HTT protein and are testing whether this is more sensitive if developed for AlphaLISA, MSD, Singulex or Simoa technologies. Once established we shall determine the relationship between somatic expansion, incomplete splicing, the exon 1 HTT protein and HTT aggregation in brain regions and peripheral tissues during the course of disease in the zQ175 knock-in HD model. To complement the work of the Tabrizi lab, we plan to use mouse models to investigate the extent to which targeting somatic CAG expansion or lowering the levels of the Httexon1 transcript might have therapeutic benefit. We are attempting to import a mismatch repair line that can be used to ablate CAG repeat expansion in a well-characterized mouse model of HD, to determine the maximum benefit of this approach, and set a baseline against which all future therapeutic approaches targeting DNA repair can be measured. We shall also be able to compare this to approaches directly targeting HTT transcripts as we have a number of reagents (ASOs, siRNAs and U1 adaptors), at various stages of development, that can be used to lower the levels of the Httexon1 and the full length HTT transcript.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Neural system failure in demen
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Ageing is a central challenge for our societies. Old age carries a high risk of dementia – a condition that is so far neither preventable nor curable. The most common cause of dementia is Alzheimer’s disease (AD). AD is manifest by widespread accumulation of amyloid plaques and tau containing neurofibrillary tangles in the brain. While we know a lot about these molecular and pathological alterations, we still lack an understanding of the cellular and circuit changes that underlie the progression and the symptoms of AD. It is, for example, unknown why, how and when people affected by AD pathology lose the ability to form new memories. The goals of the current application are to develop new ways to directly examine the brain as it starts to begin to develop pathology, using a combination of cutting-edge in vivo microscopy and electrophysiological techniques and novel animal models. The ultimate goal is to identify new therapeutic opportunities and targets to protect cells in the brain from the ravaging effects of tau and amyloid.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Neuroimmune role of microglia
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Microglia, the resident immune cells of the central nervous system, are active participants in brain wiring. They sculpt and refine neural circuits, and influence synaptic development and function. In multiple disease models of synapse loss and dysfunction, including Alzheimer’s disease (AD), microglia aid the breakdown of synaptic circuitry (Hong et al., Science 2016, Vasek et al., Nature 2016, Lui et al., Cell 2016 and Dejavonic et al Neuron 2018). Altogether, these findings raise the need to understand the immune basis of neurologic function and circuitry. However, remarkably little is known about how microglia communicate with neurons and whether microglia contribute to circuit-specific function in the adult brain. We still know very little about underlying mechanisms of microglia-synapse interactions. Whether microglia, or other immune cells, contribute to adult brain homeostasis and neuronal function in the adult brain are virtually unknown. Furthermore, emerging literature suggests diverse states of microglia, raising the need to understand what functional states microglia assume, and whether there is a region- or circuit-specific microglial heterogeneity that underlies brain wiring and function in the healthy brain and vulnerability to dysfunction and loss in the diseased brain. Goals of my laboratory will be to understand the immune–synapse interactions in the adult brain and how these are altered with physiological (activity or experience) or pathological (Aβ or alpha-synuclein) stressors. First, we aim to how synapses are targeted for elimination by microglia. Experiments will help us gain a detailed molecular portrait of microglia and what makes synapses vulnerable. Second, we aim to study whether and how microglia contribute to higher cognitive functions, i.e. memory. We aim to study subpopulations of microglia uniquely associated with specific circuits or behavior, and how microglia impact one’s ability to learn a task or remember. Third, we are interested in understanding how the peripheral immune signalling contributes to microglial and synaptic biology in the adult brain. The experiments we propose will broaden our understanding of how the immune system and the nervous system work together to maintain brain function, and how these interactions may go awry during aging and dementia. As region-specific vulnerability is a hallmark of many neurologic diseases, our proposed experiments have the potential to reveal mechanistic insight fundamental to synaptic and neuronal function and health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Structure-function relationsh
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. The Bartels lab is trying to understand the folding mechanisms of so-called “intrinsically disordered” proteins in vivo. These proteins are characterized by domains predicted to be largely structure-less, yet they are common in eukaryotic organisms (27–41%), leading to a puzzling disconnect in the protein structure = function paradigm. My focus has been on the structures of α-Synuclein (αSyn), a protein previously believed to be “natively unfolded” that is involved in the pathogenesis of Parkinson’s disease (PD), as well as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA), so-called “synucleinopathies”. To study the structure of αSyn, I broke the usual paradigm of doing structural analysis in recombinant systems and isolated αSyn under non-denaturing conditions from human tissue. I demonstrated that this previously labelled “natively unfolded” protein exists in a highly structured tetramer that is resistant to disease-associated misfolding, meaning that destabilizing this tetramer is an early requirement of pathogenesis in neurodegeneration. These findings forced a re-evaluation of 15 years of previous work on αSyn, opening new avenues for therapeutics and biomarkers for the treatment of PD that I am actively exploring under a filed patent. Furthermore, αSyn is one of the most prevalent examples for “intrinsically disordered” proteins (IDPs). Since we were able to demonstrate that context specific structure formation is highly relevant for synucleinopathies, my lab has started elucidating diverse context-dependent mechanisms for IDPs that are leading to functional structures in living cells but not in the classical in vitro systems where important cellular components are missing. This has the potential to provide insight into the basic biology of this interesting class of proteins, many with a strong connection to neurodegeneration (e.g., TDP-43, PrP, Tau). I believe that in these proteins, pathways driven by kinetics, not necessarily thermodynamic stability, are important for what functional and pathogenic forms are present in a living cell. Therefore, understanding these pathways will ultimately be key to understand the molecular mechanisms of the neurodegenerative diseases associated with these proteins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL