NIHRDataInsights/HRCSData huggingface dataset:
Title: The relationship between progenitor populations and the organisation of local excitatory synaptic circuits within the mammalian cortex.
Funder: Wellcome Trust

Abstract: A fundamental question in neuroscience is how neurons establish their functional identity and specific synaptic connections with other cells. However, we still know very little about how, or when, the functional identityand connectivity of an individual neuron becomes constrained during its development. Recent technical advances now make it possible to label differentpopulations of neurons in the brain, and this work has generated exciting discoveries into the processes by which neurons form functional networks. Herewe will build upon the observation that excitatory cortical neurons are generated from multiple progenitor pools within the ventricular zones of the embryonic brain. Using the somatosensory cortex of the mouse as a model system, the goal of this project is to investigate the extent to which synaptic connectivity within and between layers of the cortex are influenced by the particular progenitor population from which neurons are derived. We will focus upon layer 2/3 pyramidal neurons, which are the most abundant cellsof the cortex. Experiments will assess whether layer 2/3 pyramidal neurons derived from a population of so-called 'short neural progenitors' (SNPs), which express the transcription factor alpha-tubulin 1 (T?1), exhibit distinctpatterns of synaptic connectivity when compared to layer 2/3 pyramidal neuronsderived from other progenitors.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: In vivo and in vitro guidance of developing neurons by mechanical cues.
Funder: Wellcome Trust

Abstract: Neuronal growth is essential for nervous system development and is required for regeneration after nervous tissue injury. The molecular cues that guide axons and dendrites towards their targets have been extensively characterised.Recent studies, mostly in vitro, also suggest that growth of neuronal processes may be regulated by the mechanical properties of their substrates; however, the role of tissue mechanics in axon pathfinding in vivo is still largely unknown. The overall goal of this project is to determine how mechanical factors affect axon guidance in vivo during early development, using retinal ganglion cell (RGC) axon outgrowth in the Xenopus embryo as the model system. The project will combine techniques from biology and physics togenerate quantitative descriptions of the spatiotemporal dynamics of tissue stiffness along the developing optic tract, and determine if this is functionally significant for RGC axonal pathfinding. Ultimately, the results obtained could broaden current understanding of axon guidance, which may in turn be important for research into neural regeneration, as well as


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of c-Jun in controlling the repair-supportive phenotype of Schwann cells in injured nerves.
Funder: Wellcome Trust

Abstract: Work in the Jessen and Mirsky laboratory, using a mouse in which the transcription factor c-Jun has been inactivated in Schwann cells only (c-Jun-cKO mouse), shows that the Schwann cell response to nerve injury depends on activation of the transcription factor c-Jun in Schwann cells, and that this protein specifies the phenotype of the Bunger repair cell, a cell essential for nerve regeneration. Consequently, nerve repair is severely compromised in c-JuncKO mice. This project will address the following issues: 1) Establish an in vitro model of the regeneration deficit in c-Jun-cKO mice, using adult DRG neurons and Scwann cells from injured nerves. 2) Use this model to analyse Schwann cell factors that control axon growth and neuronal survival. 3) Test whether axonalregeneration and neuronal survival can be improved by enhancing Schwann cell c-Jun expression. 4) Determine whether the diminishing ability of distal nerve tosupport repair with time after injury ( the deterioration of the distal stump ) is due to instability of the Bungner repairsupportive phenotype, and its gradual attenuation. 5) Test whether the repair-supportive Schwann cell phenotype


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Development of diencephalic asymmetries in zebrafish and chick embryos.
Funder: Wellcome Trust

Abstract: While most of the body is symmetrical with respect to the midline, a few functions, including higher order behaviours and cognitive functions in the brain, have evolved to be concentrated on one (left or right) side. Although the molecular mechanisms underlying left/right asymmetry of body organs are now fairly well understood, we still know little about how lateralised brain functions arise during development. Recent research has discovered that the parapineal, an asymmetrically positioned group of neurons in the left diencephalon, is essential for development of asymmetries in the adjacent epithalamus, but little is known about the molecular mechanisms of this regulation. Also, no region equivalent to parapineal has yet been discovered in most vertebrates including birds and mammals, whereas the molecular pathways leading to epithalamic asymmetries are likely to be conserved. This project explores how epithalamic asymmetries develop in two different species - zebrafish and chicken, first by establishing the molecular mechanisms by which the parapineal regulates this process in zebrafish, then by studying


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Investigating the different roles of interneuronal populations in modulating cortical dynamics
Funder: Wellcome Trust

Abstract: Normal and pathological brain activity is characterised by changes in brain rhythms. Such changes are linked to attention, sleep-wake cycles, or epilepticseizures. During an epileptic seizure, for example, there are a series of transitions which are often highly stereotyped in individuals, and which may be pathognomonic of the seizure type. There are various animal and computational models for generating oscillations in specific frequency bands. However, the transition between frequencies is not well understood. Cortical layers might show distinct frequencies that interact and lead to altered frequencies in following time steps. Furthermore, input from thalamus, corpus callosum or adjacent cortical areas might trigger frequency transitions. This project will use optogenetics to change input and on-going activity in specific circuits to test their influence on frequency transitions. Experiments will be complemented by computational models of cortical circuits to better understand on-going dynamics and inform the selection of future targets for experimental stimulation. This work will not only be important in assessing transitions in epilepsy (e.g. from the inter-ictal to the ictal stage), but also for models of external interventions to change pathological brain rhythms in the future.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Analysis of the Leucine Rich Repeat domain of Leucine Rich Repeat Kinase 2 andthe role of TLR4 mediated innate immune si nallin in Parkinson's Disease
Funder: Wellcome Trust

Abstract: Parkinson's Disease is a chronic neurodegenerative disease characterised by destruction of dopaminergic neurones within the substantia nigra pars compacta region of the midbrain. This project aims to elucidate molecular mechanisms underlying Parkinson's pathology. One avenue of research involves expression, purification and analysis of the leucine rich repeat domain of 'Leucine Rich Repeat Kinase 2' (LRRK2), a molecule found to be strongly associated with Parkinson's disease by genome wide association studies. I aim to continuemy rotation work, purifying the leucine rich repeat domain of Leucine Rich Repeat Kinase 2with the ultimate aim of identifying ligands which interact with this domain, and performing x-ray crystallographic analysis for structural determination. A further line of research involves the identification of TLR4 agonists which may be involved in Parkinson's pathology in the absence of infection. I aim to purify such agonists for use in an NFKB assay to monitor TLR4 activation. I then aim to compare differences in the profile of endogenous TLR4 agonists between the wild type and Parkinson's brain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Network Informed Investigation of Evolutionary Conserved Neuronal Transport Processes.
Funder: Wellcome Trust

Abstract: Neuronal function is dependent on the appropriate conditional release of neurotransmitters at synaptic and motor neurone junctions. The molecular transport processes and regulated secretory mechanisms required to facilitate appropriate synaptic transmission are complex multi-stage events and defects at any step of these pathways may result in chronic or progressive neuropathies, including myasthenia gravis, schizophrenia [1] or neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) [2] and Alzheimer's disease [3]. Although the fundamental mechanisms of vesicular transport, neurotransmitter release and endocytic recycling are known, there are many aspects of molecular organisation and regulation that remain unclear.Previous work in the Sanderson lab has identified around 50 novel proteins that are required for effective neurotransmission in C. elegans. This project aims to combine informatics and experimental methods to validate and characterise the role of these proteins, in both C. elegans and mammalian cells. Initially, protein interactions involving novel orthologous human proteins will be analysed using established yeast-2-hybrid (Y2H) methods. The dynamic composition and molecular architecture of the identified protein complexes will then be investigated in mammalian cells using advanced FCCS imaging techniques. Selective 'edgetic' effects of disease-related mutations will also be tested, to provide new insights into the molecular mechanisms of associated neurological disorders. Finally, an improved annotated protein interaction network for evolutionary conserved neuronal transport will be submitted to the IntAct database as an open access public resource.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: HSP Net: Investigating the molecular mechanisms of HSP neuropathies.
Funder: Wellcome Trust

Abstract: Hereditary spastic paraplegias (HSPs) are a genetically diverse group of disorders that share the clinical feature of progressive lower limb spasticityand pyramidal weakness caused by distal axonopathy of corticospinal tract axons. Although increasing numbers of HSP linked genes are being identified, many HSP related proteins remain poorly characterised with few known interaction partners. As such, the molecular mechanisms of HSP progression remain poorly understood. To address these issues we aim to generate a verified high-density HSP protein interaction map, to provide new insight intothe molecular defects that contribute to HSP development, or the rate of disease progression. Initially, high-throughput Y2H methods will be used to perform large-scale interactome studies for all known human HSP-related proteins. Novel protein interactions will then be investigated in mammalian cells/neurons to define the distribution, dynamics, KD and size of HSP-containing protein complexes, using advanced FCCS based imaging techniques. Domains required for specific partner interactions will be assessed by Y2H and FCCS methods and selective 'edgetic' effects of disease related mutations will also be investigated. This information will provide valuable insight into pathogenic processes that contribute to different HSP neuropathies and may aid future development of better 'stratified treatments' for these conditioned.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Modulating hippocampal neurogenesis to restore learning and memory in mesial temporal lobe epilepsy.
Funder: Wellcome Trust

Abstract: Learning and memory dysfunction is the commonest neuropsychological effect of mesial temporal lobe epilepsy (mTLE). Because the underlying neurobiology is poorly understood, there are no pharmacological strategies to restore learningand memory function. Neurogenesis in the adult dentate gyrus is important for allocentric hippocampal learning, is impaired in chronic mTLE due to chronic neuroinflammation, and we have recently shown thatrestoring neurogenesis in animal models returns allocentric learning to normal. Using 30 cultures of sclerotic hippocampus from epilepsy surgery patients we also show that this antineurogenic effect is Q£!1!y mediated via IL-1beta release. Cytokines released into the stem cell microenvironment from astrocytes, neurons and microglia are key modulators of neurogenesis under normal and neuroinflammatory states and are also primed by the complement system. Status epilepticus induced epigenetic modification of hippocampal neural stem cells also appears to play a role bothin normal and in chronically altered neurogenesis in mTLE. Our objectives are to examine the role of cytokines, the complement system andepigenetic modification in generating and maintaining the anti-neurogenic niche in animal models and human mTLE, and whether these affect hippocampal learning, in order to identify drug targets for treating cognitive impairment in human mTLE.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Generation and characterisation of cortical interneurons from human pluripotent stem cells
Funder: Wellcome Trust

Abstract: Inhibitory interneuron dysfunction is believed to lead to runaway excitation implicated in seizure­ based diseases, such as epilepsy. However, due to a lack of defined aetiology and causal mechanisms of the pathogenesis, there is currently no effective treatment for these conditions. The generation of neurons from pluripotent stem cells, either derived from patients carrying defined genetic variants, or engineered in culture with disease relevant genetic modifications, offer a unique path to investigate the underlying disease mechanisms. Moreover, exciting experimental cell therapy has shown that foetal-derived interneuron precursors can reverse seizure severity and reduce mortality in adult epileptic rodents. These proof-of-principle studies raise hope for potential interneuron-based transplantation therapies for treating epilepsy. Therefore, this PhD project aims to generate defined functional cortical interneurons from human pluripotent stem cells. The specific objectives are: 1, To establish an interneuron reporter cell line by genome editing in human ESCs; 2, To optimise interneuron production strategy and to perform phenotypic and functional characterisation of the derived human neurons; 3, To investigate the differentiation potential and functionality of hPSC-derived interneurons in vivo by transplantation. The anticipated outcome of this work will be the establishment of an improved inhibitory neuron differentiation regime and parameters for interneuron transplantation.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Modelling the cognitive impairment associated with Parkinson's Disease in Drosophila.
Funder: Wellcome Trust

Abstract: I aim to develop a robust model of Parkinson's disease in the fruit-fly, Drosophila melanogaster. While previous fly models of Parkinson's have been shown to recapitulate key hallmarks of the disease such as motor functional impairment and dopamine neuron loss, we aim to see if sporadic (rotenone-induced) and genetic Drosophila Parkinson's models also exhibit thecognitive impairment that is common in human patients of the disease. By incorporating electrophysiology, cognitive testing, dynamic cell imaging and fluorescent confocal microscopy I will test for the first time if Drosophila models of Parkinson's disease have the full range of pathological hallmarks of the disease. Preliminary data from the lab has shown that Drosophila Parkinson's models exhibit signs of the cognitive impairments associated with human forms of the disease. The tools, techniques and equipment previously developed in the lab will allow me to examine how theseimpairments relate to disturbance of cellularmechanisms of memory formation and synaptic plasticity. The identification of any pathological phenotype associated with Drosophila Parkinson's models will be carried out with aview to screen for genetic interventions which may reverse said pathology, with the hope of helping identify new therapeutic targets for treating the cognitive impairment of Parkinson's patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Sub-millimetre structural connectivity imaging of cortical, subcortical and spinal pathways in humans.
Funder: Wellcome Trust

Abstract: The human brain consists of two types of tissue: grey and white matter. The grey matter contains the brains processing units, whereas the white matter is akin to bundles of network cables, allowing different regions of grey matter to exchange information. Connection errors are the cause of a wide range of diseases including schizophrenia and autism. The only method available to measure the white matter bundles in the living human brain is by means of a magnetic resonance imaging (MRI) technique called diffusion imaging (dMRI). Unfortunately, at present this method depicts the connections with insufficient detail. Two bundles close together for example cannot be distinguished, nor can small connections or complex geometries. I will develop new techniques to improve the level of detail that can be assessed using MRI scanners equipped with an exceptionally strong magnet. Such scanners can in principle scan very small structures, but there are some technical challenges. By developing solu tions to these challenges, I will be able to study the connections in the living human brain and even spinal cord in unprecedented detail.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Epigenetic regulation of neuronal development through long non-coding RNAs .
Funder: Wellcome Trust

Abstract: How the rich variety of neurons present in the mammalian brain is derived from small number of neural progenitors is a fascinating question, which has only recently started to be addressed due to major advances in isolating and manipulating the different types of neurons. However, due to the limited number of protein-coding genes ( building blocks ), there is increasing realization that the non-coding part of the genome might be responsible for providing the blueprints for embryonic developmen t and especially brain architecture. In particular, a class of recently discovered non-coding RNAs called lncRNAs are quite promising in their ability to regulate different biological processes including cancer and pluripotency. However, most studies so far have been done using in vitro based approach, which can provide limited answers especially for complex organs such as the brain. Therefore, I propose to examine the functional role of this type of non-coding RNAs during neuronal developmen t using an in vivo model - the mouse cortex. Understanding the biological function of lincRNAs in neural development would be of considerable value to the field of regenerative medicine. Such knowledge could potentially lead to strategies to reverse the differentiation process or be used in cell replacement therapies in neurodegenerative diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Investigating the Regulation of Dopaminergic Neurons in C. elegans.
Funder: Wellcome Trust

Abstract: Dopaminergic neurons control many aspects of behaviour in both humans and C. elegans. Therefore unsurprisingly, major human diseases like Parkinson's and Schizophrenia are associated with the malfunction of dopaminergic neurons. The nematode C. elegans is an established model organism to address neurobiological questions like the regulation of dopaminergic neurons. The specific degeneration of these neurons is the major hallmark of Parkinson's Disease and can be recapitulated following administration of the drug 6-Hydroxydopamine (6-OHDA) in mammals and worms (Nass et al. 2010). I used this drug assay to screen for mutants which render C. elegans more susceptible to 6-OHDA-toxicity. In result, 4 hypersensitive mutants were isolated and 3 additional mutants were found that do not properly specify dopaminergic fate. The identification of the corresponding genes and their subsequent characterisation will be the focus of my PhD. To our best knowledge, there is only one other gene known so far to protect dopaminergic neurons from degeneration (manuscript in preparation) and the mutants with defective differentiation promise to contribute to the existing literature. Hence, by characterising the function and molecular mode of action of these genes we expect to make important contributions to the understanding of dopaminergic neuron biology in health and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of alpha-synuclein misfolding in Parkinson's disease.
Funder: Wellcome Trust

Abstract: Parkinsons disease is a common neurodegenerative disease affecting 1-2% of people over the age of 65. Parkinsons disease is characterized by the progressive loss of nerve cells, and the presence of abnormal protein aggregates containing the protein alpha-synuclein. Alpha-synuclein is normally a soluble protein called a monomer, but under disease conditions, it starts to misfold and associate with itself to form oligomers, and then eventually it becomes insoluble and forms fibrils. The process of aggregation of alpha-synuclein is likely to be central to the pathogenesis of PD. Until recently, aggregation has been poorly understood as it is difficult to measure and isolate the different species of alpha-synuclein that are formed during aggregation. This fellowship aims to understand the aggregation process of alpha-synuclein and how it causes cell death. It exploits a new biophysical method called single molecule FRET that allows the aggregation process to be studied in unprecedented mol ecular detail. Once the aggregation process of alpha-synuclein is understood outside the cell, it will be important to find out the effects of each species of alpha-synuclein within human neurons. This work will explain (1) which species of alpha-synuclein causes neuronal death and (2) the mechanism by which it causes neurodegeneration.


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