NIHRDataInsights/HRCSData huggingface dataset:
Title: Can we protect neurons against mitochondrial dysfunction?
Funder: Parkinson's UK

Abstract: Mitochondrial dysfunction plays an integral role in the pathogenesis of Parkinson's disease (PD), highlighted by the identification of mitochondrial gene mutations in familial PD. Despite evidence showing that the neurons of the substantia nigra (SN) are particularly sensitive to mitochondrial dysfunction, the impact of this dysfunction on cellular survival remains unclear. My previous work has shown that SN neurons can tolerate mitochondrial defects occurring early in life, whereas defects in later life cause neuronal loss. This application will build on this success to define the mechanisms by which SN neurons adapt to mitochondrial dysfunction early in life and identify drugs which would allow similar adaptation to mitochondrial defects later in life. Using a library of compounds known to affect mitochondria, I will search for candidates which facilitate adaptation in dopaminergic neurons, with a view to finding new drugs to protect SN neurons from loss. I will use three complementary systems to investigate the response of SN neurons to mitochondrial dysfunction. (1) In human tissue I will investigate the modulation of key pathways in SN neurons harbouring mitochondrial defects. (2) I will use human induced pluripotent stem cells in a phenotypic screen to identify compounds which elicit the same adaptation, protecting dopaminergic neurons against dysfunction. (3) An alpha-synuclein mouse model will be utilised to expand knowledge of the relationship between alpha-synuclein and mitochondria. This project will enable a better understanding of the mechanisms involved in the loss of SN neurons in PD and highlight new therapeutic targets to prevent this loss.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Development of new in vitro tools to study ALS
Funder: Motor Neurone Disease Association

Abstract: Dr Ferraiuolo is the holder of a Marie Curie EU-funded fellowship, whcih has enabled her to work with both Prof B. Kaspar (Columbus, Ohio) and Prof Pam Shaw (SITraN, Sheffield). From her time at the Kaspar lab, she has developed a fast method to reprogram fibroblasts, allowing differentiation of neurons, as well as the other cell types involved in ALS, i.e. astrocytes and oligodendrocytes, within about 1.5-2months after obtaining fibroblasts from patients or controls. She can also set up cultures of astrocytes and oligodendrocytes with control motor neurons expressing a green fluorescent protein. These cells enable her to easily follow motor neuron growth and death live with a sophisticated fluorescent microscope able to capture movies. This set up has enabled development of a 'high throughput' screening method to screen chemical compounds in high number and on cell lines developed from a variety of ALS cases. The work is now continuing at Sheffield, but is challenged by the high costs of maintaining sufficient cell lines. The small grant from the MND Association will allow a greater number of lines to be maintained as well as facilitating the screening of small molcules for their ability to alleviate/block astrocyte toxicity against motor neurons.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Characterising a unique mouse model with SOD1 amyotrophic lateral sclerosis and the same mutation found in human ALS families
Funder: Motor Neurone Disease Association

Abstract: This is a project grant application made by three groups working together, all of whom have expertise in different aspects of mouse models of ALS. We are combining our knowledge and wish to undertake one seamless project to analyse what we believe is a very important new mouse model of ALS. The mouse was produced in a big genetics experiment and has a mutation in the Sod1 gene that is exactly the same as a mutation, ‘D83G’, that causes ALS in humans. As with humans, we find that these mice succumb to motor neuron degeneration and to locomotor abnormalities, so they model human ALS. Unlike existing transgenic mice, these Sod1D83G animals do not have abnormal numbers of copies of the SOD1 gene, and so they are the closest thing, biochemically, to the human condition. This makes these mice very valuable for understanding disease processes and testing therapeutics, particularly in the early stages of ALS. We are asking for a postdoctoral researcher for three years to characterise this mouse strain in order to learn more of the processes that lead to ALS, and to make it freely available to the research community for basic science and for testing therapies. We will analyse this valuable mouse (in comparison to D83G human families) so that we fully understand how it relates to human ALS. We will carry out a range of highly specialised techniques in this analysis, in which we or our close collaborators have expertise. The benefits for ALS research will be the establishment of a new Sod1 mouse model with the equivalent levels of mutant SOD1 protein as those found in patients, which will be invaluable for therapy development, particularly for early stage disease, and without the confounds of high doses of SOD1 protein found in transgenic mice. We note that mutations in human SOD1 remain the most frequent source of human familial ALS and recently SOD1 has been implicated in sporadic ALS.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: New humanised delta-14 mouse model for dissecting the pathobiology of FUS-ALS
Funder: Motor Neurone Disease Association

Abstract: Motor neuron disease, also known as amyotrophic lateral sclerosis, ALS, is a progressive, incurable, neurodegenerative disease that usually affects people in mid-life, and causes death typically within 3-5 years of diagnosis. The disease causes the nerve cells, ‘motor neurons’, which run from the brain, through the spine, to the muscles, to die, leading to paralysis. ALS is untreatable and there is a dire need to understand what goes wrong in the disease, to create new therapies accordingly. One route to understanding ALS is to look at the relatively rare cases that are caused by defects in genes, the heredity units that we inherit from our parents. Several genes are now known to cause ALS when they are defective. One particular ‘ALS gene’ is called ‘FUS’. When this is defective, for unknown reasons it can cause very early onset (teens) and aggressive ALS so that young people die within a year or so of diagnosis. Understanding how aberrant FUS causes ALS will tell us a lot about ALS generally. Therefore we have created new mice that have aberrant FUS, and so ‘model’ human ALS. We have made a particularly accurate type of FUS mouse model, and we now wish to study this mouse further to (1) understand ALS with a view to future therapies, and (2) collect sufficient data for a much larger longer-term grant application. Such longer term funding is essential to enable us to capitalise on this mouse, and to understand what happens in motor neurons and other cells when FUS does not work properly. We also wish to create two new types of mice to help answer a specific question about how one aspect of FUS function affects motor neurons. All our mice will be made freely available to the research community.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Axonal transport, protein trafficking and neurological disease
Funder: Medical Research Council

Abstract: The hypothesis that underlies this proposal is that defects in axonal transport and protein trafficking are part of the pathogenic process in three familial forms of amyotrophic lateral sclerosis (ALS). These familial forms are those caused by mutations in the genes encoding copper/zinc superoxide dismutase-1 (SOD1), ALS2/Alsin and vesicle-associated membrane protein-associated protein-B (VAPB). The aim of the project is to understand how these different genetic insults induce defects in neuronal protein transport. The primary objectives are:- 1) To identify p38 stress-activated kinase phosphorylation sites in neurofilament proteins and to determine how this influences axonal transport of neurofilaments. p38 is activated in ALS, phosphorylates neurofilaments which in turn is known to be a regulator of neurofilament transport. This will be achieved by sequencing neurofilament proteins isolated from neuronal cell bodies in which we have activated p38 by transfection of dominantly-active MKK3. MKK3 is a direct upstream activator of p38. Identified sites will then be mutated to preclude or to mimic permanent phosphorylation and the transport properties of these mutants analysed by monitoring movement of green fluorescent protein (GFP)-tagged variants in transfected cultured neurons. 2) To determine whether ALS mutant SOD1 induces changes in phosphorylation of kinesin and dynein family proteins. These are phosphoproteins and there is emerging evidence that they may be substrates for p38. This will involve proteomic analyses of motor proteins isolated from cells and tissues expressing wild-type or mutant SOD1. 3) To determine how loss of ALS2 influences both fast and slow axonal transport by monitoring movement of GFP-tagged cargoes in living neurons derived from wild-type and ALS2 knockout mice. 4) To gain insight into the mechanisms by which ALS2 may signal to regulate axonal transport and how phosphorylation of ALS2 influences any such signalling. 5) To characterise new transgenic mouse models expressing ALS mutant VAPB that we have recently generated. 6) To determine whether ALS mutant VAPB damages axonal transport and if so, to gain insight into the mechanisms that underlie this effect. The studies will thus provide information on the mechanisms underlying defective axonal transport in ALS and may reveal new therapeutic targets for this disorder. Since disruption to axonal transport is seen in other neurodegenerative diseases, these results are likely to be informative about pathogenic processes in a number of these disorders.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cerebellar circuitry: from synapse to behaviour
Funder: Medical Research Council

Abstract: The cerebellum makes motor adjustments and sensorimotor predictions essential for any kind of active life. Cerebellar disorders have severe effects: impairment of balance (ataxia) and extremity coordination (dysmetria), disordered eye movements (nystagmus), dysarthria and intentional tremor. The cerebellum offers an opportunity for understanding how neuronal networks produce and store memories. Three outstanding advantages are: (i), the well defined circuit; (ii) the ability for precise cell-type specific targeting using gene promoters; (iii) a new pharmaco-genetic technique that we have invented for fast cell-type specific modulation of neurons in vivo. This enables dynamic analysis of individual circuit components and how they relate to, or produce, behaviour. We wish to: (i) investigate how feed-forward inhibition of the Purkinje cells shapes cerebellar memories, in particular the consolidation process; (ii) explore the possibilities of cell-type selective bidirectional modulation of Purkinje cells ? can we increase or decrease memory performance; (iii) explore the role of the timing component of inhibition (phasic inhibition) onto granule cells using specific modulation of the Golgi-granule cell synapse using newly engineered mice; (iv) explore the role of mossy fibre input to granule cells by specifically ablating either the AMPA or the NMDA receptor component. We will study these questions using slice and in vivo electrophysiology as well as behavioural assays.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Stem and progenitor cells of the postnatal CNS
Funder: Medical Research Council

Abstract: We showed recently that the adult forebrain subventricular zone (SVZ) contains a mixture of stem cells that have spatially diverse origins in the embryonic telencephalon and different neurogenic properties in the adult. We shall use genetically manipulated mice to dissect the roles of these different SVZ stem cell sub-populations in adult olfactory neurogenesis and olfactory behaviour, and their possibly distinct regenerative responses to damage. There are also stem cells in the adult spinal cord ependymal zone (EZ) surrounding the central canal. By analogy with the SVZ, the EZ might be expected to inherit the spatially patterned cell fate restrictions of the embryonic neuroepithelium. We will test this by mapping the embryonic origins of the EZ and asking whether embryonic ancestry predicts adult stem cell response to degenerative disease (a genetic model of motor neuron disease), demyelination or physical injury. Finally, we shall examine the role of ?NG2 cells? ? an abundant and ubiquitous population of progenitor cells in the adult CNS ? in adult gliogenesis and cortical neurogenesis, testing the ideas that de novo myelination of previously naked axons contributes to neural plasticity and that adult-born cortical projection neurons likewise have a significant functional role.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: New mouse models for tackling motor neuron disease and other neurodegenerative disorders.
Funder: Medical Research Council

Abstract: Amyotrophic lateral sclerosis (ALS) is mostly (~80%) sporadic but familial forms (FALS, ~20%) are known. The SOD1 gene is the most common causative gene for FALS, and recently rare mutations have been identified in the TDP43 gene. This is of interest because TDP43 is the major ubiquitinated protein in inclusions in both sporadic and familial ALS ? although not SOD1 related ALS. We are requesting funding for one postdoc and one technician (minimum staffing to make this application realistic) to create two novel mouse strains modelling amyotrophic lateral sclerosis (ALS) with the SOD1 human genomic coding region knocked in, and two novel strains with a human TDP43 cDNA knocked in. These mouse strains are essential for understanding ALS because: if the knock in mice have a mid-life disease, this would arise from mutation, not from overexpression of the transgene array, which is known to have an effect in existing SOD1 transgenics; the model is physiologically more relevant than existing transgenics, giving us a better understanding of pathology and a better model for conventional and gene therapeutics ? including siRNA and lentiviruses; this model also gives us a better knowledge of the protein interactions that occur in ALS because it is biochemically more relevant to the human disease; this model helps address the biophysics/biochemistry of mutant:wildtype dimers and enzyme function, in a variety of primary cell lines, including embryonic stem cells and motor neurons; a mouse with late onset disease will direct us to biomarkers, desperately needed by ALS clinicians. Critically, we will make Cre-conditional knock in mice in which the mutation can be turned off in any tissues ? thus informing us, for example, about motor neuron ? glia interactions as we already know SOD1 induced motor neuron death is not cell autonomous and therefore glia and other cells may be targets for therapy. We wish to make knock in mice for both mutant SOD1 and TDP43, because although mutations in these genes may feed into a final common pathway, the lack of TDP43 pathology in SOD1 mutant ALS clearly shows the genes have different initial effects. A critical feature of this award is that we will make the mice freely available immediately, via the European Mutant Mouse Archive and the Jackson Laboratory, for distribution to all interested laboratories.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Defining diseases and tracking progression in frontotemporal lobar degeneration
Funder: Medical Research Council

Abstract: Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases that collectively constitute a common cause of young onset dementia and a substantial source of human, clinical and socio-economic hardship. If disease-modifying therapy for FTLD is to be realised, robust biomarkers of disease onset and progression and accurate diagnosis and stratification of FTLD subtypes informed by emerging information about disease mechanisms will be required. Here we propose a comprehensive 5 year longitudinal programme of research designed to identify and validate biomarkers of disease onset and progression in FTLD and its subtypes, and to assess their translational potential to other health care delivery and clinical trials settings. The specific aims of the programme are to assess biomarkers of earliest disease manifestation through the study of at-risk individuals; to assess biomarkers of disease progression; to classify diseases and disease subtypes; and to evaluate novel techniques and disease mechanisms To address these aims we will recruit from an established large longitudinal cohort of FTLD patients, and in particular, presymptomatic and ?at risk? individuals from a number of genetic FTLD pedigrees, allowing detection and tracking of earliest disease manifestations. We will draw on a successful track record of developing and applying innovative and translatable image analysis techniques and novel neuropsychological instruments to define and track neurodegenerative diseases. The programme will capitalise on established collaborations with partner laboratories in image computing, tractography, functional brain imaging, neurogenetics and neuropathology. Subjects entering the study will be assessed prospectively and longitudinally with detailed clinical evaluation, neuropsychology, structural and functional MRI, and post mortem data on patients with FTLD whom we have followed historically will be correlated retrospectively with candidate biomarkers to assess their predictive and neurobiological validity. A suite of techniques will be used to analyse behavioural and imaging data, including linear and nonlinear registration, tractography, cortical thickness and unbiased voxel-based pattern recognition and morphometric techniques, with particular emphasis on techniques with diagnostic and translational potential. Mixed linear models and multivariate statistical techniques will be applied to the identification and evaluation of candidate biomarkers. The programme will yield robust, generalisable and novel biomarkers of disease onset, evolution and classification in FTLD, and offers significant follow-on opportunities for guiding clinical trial design and shaping health care delivery in young onset dementia.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Investigation of Heat shock Factor 1 as a Therapeutic Target for Huntington s Disease
Funder: Medical Research Council

Abstract: Within the aging populations of the developed world the health, social and economic burden of neurodegenerative disease is already substantial and expected to increase. The occurrence of the most common neurodegenerative disorders: Alzheimer?s disease (AD), Parkinson?s disease (PD) and amyotrophic lateral sclerosis (ALS) is largely sporadic, however, rare familial cases of these diseases, together with inherited monogenic disorders such as Huntington?s disease (HD) have provided clues to their aetiology. In AD, PD, ALS and HD, mutations result in the propensity of disease-associated proteins to misfold, form a-sheet structures and become ?aggregation-prone? properties for which they have been named ?protein-folding? diseases. In all cases, disease-modifying therapies do not exist. All cells maintain protein-folding homeostasis through integrated protein-folding and clearance networks and pathways. Molecular chaperones direct the folding of newly synthesised and damaged proteins and those that cannot be successfully folded into their native conformation are degraded through the ubiquitin proteasome system (UPS) or cleared by lysosome-mediated autophagy. In the presence of an aggregation-prone protein, the mechanisms that maintain protein folding homeostasis become overwhelmed resulting in misfolding and aggregation. The capacity to maintain protein folding homeostasis diminishes with age, resulting in an increasing susceptibility to protein folding disease in the elderly. Strategies that might decrease the propensity of an aggregation-prone protein to misfold include increasing either the protein folding or protein degradation capacity of the cell. One possible approach is to induce the cellular stress response. Conditions of cellular stress including elevated temperature and oxidative damage activate the heat shock response which results in the immediate induction of heat shock proteins that encode molecular chaperones and other proteins important for the recovery from stress induced protein damage. Heat shock factor 1 (HSF1) is the master regulator of the heat shock response and can be activated pharmacologically by inhibition of Hsp90. We shall use complimentary approaches: exposure to elevated temperature, administration of a brain penetrant Hsp90 inhibitor and the generation of mice expressing an inducible form of activated HSF1 to define the neuronal heat shock response in vivo and to determine whether activation of HSF1 can alleviate disease-related phenotypes in a mouse model of HD. Thereby, we shall validate whether HSF1 activation is a rational therapeutic target for HD, and by extension, other protein-folding neurodegenerative disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Nano-diffusion in the brain: mechanisms and implications examined with time-resolved fluorescence anisotropy imaging
Funder: Medical Research Council

Abstract: Rapid diffusion of small signalling molecules in the brain extracellular space determines activation of receptors and ion channels expressed on the surface of neurons and glia. The underlying mechanisms shape both synaptic and extrasynaptic actions of fast neurotransmitters such as glutamate or GABA, thus contributing to signal integration properties at all levels of neural communication, from individual synapses to cognitive activity, in health and disease. Our aim is to understand mechanisms that control instantaneous molecular mobility and thus impinge on basic determinants of rapid neural signalling. To achieve this, we will integrate a recent technological breakthrough in photonics, time-resolved fluorescence anisotropy imaging (TR-FAIM), to experiments in organised brain tissue, initially ex vivo and subsequently in vivo. Our pilot data provide proof of feasibility for this approach. Firstly, we will apply TR-FAIM to map, for the first time, the nanoscale extracellular molecular mobility in selected brain areas, including hippocampal formation and the cerebellum. Secondly, we will determine the role of the extracellular matrix, by specifically removing its essential polymeric components, in modulating such mobility. Thirdly, we will relate these mechanisms to neurotransmitter signalling and cell excitability including pathological hyper-excitability associated with epilepsy. Finally, and in longer term, we will attempt to use TR-FAIM to monitor instantaneous mobility of genetically-labelled receptor subunits (initially glutamate receptors) on the neuronal surface, to address fundamental issues of receptor diffusion, trafficking, trapping and recycling in organised tissue.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: NEUROLOGICAL