NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of an Institute of Neurology Next Generation Sequencing Facility Equipment Grant.
Funder: Wellcome Trust

Abstract: In the past the search for disease causing mutations and genetic risk has mainly been limited by the technical feasibility. The development of high-throughput sequencing machines (next generation sequencers, NGS) that can rapidly analyse genetic material in an economical way has given geneticists the route towards the complete examination of genetic factors. We wish to apply this technology to neurological disorders as a core resource at the Institute of Neurology (ION). This proposal is for a high throughput NGS, data storage and a dedicated technician. We already have experience with Illumina sequencing and have obtained high quality pilot data. At the ION we are in a strong position to exploit NGS having some of the largest patient cohorts with neurological disease in the world. For many years ION has been at the forefront of neurogenetics research, identifying disease genes and risk factors. Furthermore, we have directed or been collaborators on the majority of genomic searches for the common causes of neurological disorders. To take full advantage of this patient resource NGS will be critical in the identification of the actual disease-causing variants. The key objective of this proposal is to develop NGS as a core resource to investigate neurological disorders.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL
Title: Neuropharmacological modulation of functional brain imaging signals in awake and anaesthetised rats
Funder: Wellcome Trust

Abstract: One of the most exciting advances in the study of the brain over the last few decades is the development of brain imaging tools that allow us to capture images of the human brain at work . However, we now need a much better understanding of where the signals that are used to create these images come from and what they really tell us about the activity of groups of brain cells. Specifically, we know very little about how to interpret brain imaging signals when they originate from structures deep within the brain, or how changes in the levels of important brain chemicals affect the meaning of brain imaging signals. We propose to make measurements of the activity of brain cells in deep brain structures at the same time as recording brain imaging signals to allow us to better understand the relationship between the two. We will then see how this relationship is altered by changing the levels of serotonin, a brain chemic known to be important in normal brain function and diseases such as depression. The findings of this work will improve the way in which we can use brain imaging tools to help us understand human health anddisease.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: NEUROLOGICAL
Title: Activity-dependent trafficking of mitochondria to synapses by Miro1.
Funder: Wellcome Trust

Abstract: Nerve cells send signals to each other by releasing chemicals called neurotransmitters at special sites called synapses. The neurotransmitters act on special proteins (receptors), allowing ions to cross the cell membrane, thus producing voltage changes across the membrane. For neurons to continue signalling to each other, it is essential that they pump the ions back across the membrane, and for this they need a constant energy supply, generated by microscopic power stations within the cell calle d mitochondria. This application is on two key aspects of brain function: (i) how neurons regulate the number and position of the energy producing mitochondria near synapses and taylor this to changes in nerve cell activity and (ii) how the correct distribution of the mitochondria impacts on correct neuronal development and the formation and function of the synaptic connections. Studying the mechanisms that underlie these regulatory processes will allow us to understand better how the brain wor ks under healthy conditions, and how dysregulation of these processes leads to altered neuronal development and nerve cell survival in disease. These studies will improve our understanding of diseases in which synaptic and mitochondrial function are disrupted, such as stroke, Parkinson s disease, Alzheimer's disease, Huntington's disease and epilepsy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: In-vivo and in-vitro studies of Copper and Alzheimer s Disease; Amyloid-beta assembly and neuro-toxicity.
Funder: Wellcome Trust

Abstract: Fundamental to Alzheimer s disease (AD) is the accumulation of protein deposits known as amyloid plaques around neuronal cells. Fibrils of a small peptide molecule, the amyloid-beta peptide (Ab), are the main constituent of these plaques. Furthermore, the amyloid-beta peptide in an oligomeric or fibril form has been shown to be toxic to neurons. Animal models of Alzheimer s disease suggest a loss of regulation of the essential, yet potentially toxic, mineral copper is fundamental to Alzheimer s disease pathology. Although the link between amyloid-beta peptide and Alzheimer s disease is clear, the mechanism by which amyloid-beta peptide might cause cell toxicity is not well understood. One popular hypothesis of toxicity involves the generation of reactive oxygen species, with copper being the probable source of these reactive oxygen species. In this study we propose to investigate the influence of copper ions on the rate at with toxic amyloid-beta peptide oligomer and fibers are formed and the neuro-toxic effect of copper bound to amyloid-beta peptides has on neuronal cell cultures and genetically modified flies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cell type specific dissection of HCN1 channel contribution to cerebellar output and motor behaviour.
Funder: Wellcome Trust

Abstract: The brain contains many different types of nerve cell. It has been known for some time that these different types of nerve cell respond in different ways to signals from upstream nerve cells. However, while this is likely to be of considerable importance, very little is known about how this diversity of response mechanisms contributes to brain function. This study will address this issue by using molecular techniques to manipulate, in genetically defined populations of nerve cells, an important type of ion channel called HCN1, which controls how certain nerve cells respond to signals from upstream nerve cells. We will examine how cell type specific manipulation of HCN1 modifies execution of movements and encoding of information by neurons important for movement. We expect these experiments to reveal new and fundamental insights into how responses of particular types of nerve cell contribute to representation of information in the brain and to behaviour. This is important for understand ing how molecules enable brains to function and for clinical disorders thought to involve HCN1 channels or deficits in coordinated movement.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Zinc finger nuclease-induced homologous recombination in zebrafish.
Funder: Wellcome Trust

Abstract: The zebrafish is a major experimental model organism, with huge potential in developmental and functional neuroscience. Yet it lacks an efficient technology for generating null and conditional alleles in identified genes of interest. We propose to develop a technological platform to generate these alleles, using the newly-described zinc finger nuclease (ZFN) approach. Our field needs an array of mutations, both to ascertain results from, and complement, antisense approaches; and to address gen e function in late brain developmental stages. We wish to develop a centralized facility using the ZFN approach to generate targeted knock-out and knock-in mutants in zebrafish for the study of brain, spinal cord and neuromuscular development and diseases. The aims are twofold: i) creating a platform providing high-throughput mutations (80 genes in three years) in genes coding for key players in neurobiology; and ii) improving the technology by developing ZFN-induced homologous recombination i n vivo, thereby building conditional loss of function. This initiative is greatly encouraged by colleagues around the UK and abroad (support letters in Additional Info), and is of key interest not only for zebrafish researchers but also for laboratories using other model organisms, such as mouse and chick.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Delineation of brain-derived-neurotropic factor (BDNF) neurons modulating energy balance.
Funder: Wellcome Trust

Abstract: Aim 1: (a) To characterize the regulation of hypothalamic brain-derived-neurotrophic factor (BDNF) expression by serotonin and melanocortin compounds and (b) determine whether BDNF is required for serotonin and melanocortin compounds to elicit effects on energy balance. Aim 2: To characterize the effect of ventromedial nucleus of the hypothalamus (VMN) steroidogenic factor 1 (SF-1) BDNF-expressing neurons on the effect of serotonin and melanocortin compounds modulating energy balance. Aim 3: To characterise the specific effect of VMN SF-1 BDNF-expressing neurons on energy balance.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Translational Neuroimaging in Huntington's Disease: The effect of aerobic exercise on brain structure, function and cognition
Funder: Wellcome Trust

Abstract: 1. To develop protocols for a number of magnetic resonance imaging (MRI) endogenous contrast agents for detailed assessment of structure and physiologyin Huntington's disease (HD) patients 2. To discover MRI strategies that can provide clinical readouts in HD 3. To understand the underlying substrate change in HD patients compared to controls 4. To derive preliminary understanding of the neurobiological effects of exercise in HD 5. To understand how research translates bi-directionally between humans and animals


Research activity codes: 5.7 PHYSICAL;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Refinement of the Stroke Animal Model to Further Develop Therapeutic Strategies for Functional Repair and Treatment by Neural Transplants
Funder: Wellcome Trust

Abstract: The main aim of this project is to examine the role of the imprinted cyclin dependant kinase inhibitor gene, Cdkn1c, in neural development and the resultant behaviour in adult animals when the copy number of Cdkn1c is altered. Furthermore we will assess how manipulation of maternal environment during pregnancy interacts with Cdkn1c expression in the normal animal and how this affects midbrain structure and animal behaviour.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Role of ascending cholinergic and monoaminergic systems in absence epilepsy
Funder: Wellcome Trust

Abstract: The expression of absence seizures in humans and experimental models strongly depends on the behavioural state. However, the precise contribution of different neurotransmitters that control vigilance states to the generation of these non-convulsive seizures is still controversial, mainly because of the inability to selectively manipulate these neurotransmitter systems using conventional tools. Using an optogenetics approach that will allows us to excite or inhibit neuronal populations with high temporal resolution and strong cellular selectivity, the aim of this project is to investigate the effect(s) of the cholinergic (Ach), noradrenergic (NA) and serotoninergic (5HT) systems in the generation and maintenance of absence seizures in well established mouse models of this neurological disease. The results of this study will further our understanding of the role(s) of these neurotransmitters in absence seizures, and may lead to the identification of novel therapeutic targets for the treatment of absence epilepsy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The Charcot-Marie-Tooth diseases and associated defects in membrane transport.
Funder: Wellcome Trust

Abstract: Peripheral nerve diseases (peripheral neuropathies) are common, affecting around 2.4% of the whole population at any one time. Peripheral nerves carry information from the brain and spinal cord to the muscles, and also relay sensory information in the opposite direction. Therefore, patients with peripheral neuropathies will experience weakness, pain and numbness resulting in severe disability. Peripheral nerves are composed of two elements; axons that extend from the spinal cord all the way t o the muscles, and the supporting Schwann cells that wrap around the axon to form the myelin sheath needed for efficient conduction of nerve impulses. I aim to investigate the Charcot-Marie-Tooth diseases (CMT), which are inherited peripheral neuropathies caused by abnormal genes. I plan to determine why mutations in a particular gene, SH3TC2, that causes a subtype of CMT (CMT4C), lead to Schwann cell and myelin damage with resulting severe clinical disability. I will do this by investigati ng how the Schwann cell transports material within the cell, a pathway that I believe is abnormal in CMT. My hope is that by understanding what goes wrong in these inherited diseases, new treatments may be developed to arrest, or even reverse, the damage seen in all types of peripheral neuropathy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cue-induced translational control in axon path finding.
Funder: Wellcome Trust

Abstract: The project aims to understand the mechanism of cue-induced local translation in growing axons and how it contributes to axon navigation in the developing visual system. The objectives are:- (i) Identification of transcripts translated in response to specific guidance cues (ii) Discovery of potential regulatory networks for attractive versus repulsive guidance (iii) Investigation of the logic of cytoskeletal regulatory protein translation (iv) Testing the role of cue-induced synthesis for growth cone turning in vivo


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: An investigation into the neurophysiological biomarkers of Parkinsons disease in closed loop deep brain stimulation.
Funder: Wellcome Trust

Abstract: Parkinson s disease (PD) is unfortunately a common, disabling, progressive condition characterised by severe problems with movement for which medical treatment in the longer term is unsatisfactory. Deep brain stimulation (DBS) is an effective treatment which directly stimulates the nerves affected inside the brain to help overcome the difficulties with action. However, this treatment is currently limited by costs, side effects and a partial treatment effect. This project aims to improve DBS t reatment through building a better understanding of how PD results in problems with movement at the neural encoding level. We want to identify novel specific electrical markers of PD that can be recorded from the DBS electrodes, correlate these with the different movement problems encountered and test whether these markers remain reliable during stimulation. Subsequently, we intend to apply these new techniques in other conditions that employ DBS including Dystonia, Tourettes syndrome, pain diso rders and psychiatric conditions. Finally, we plan to use these new electrical markers of PD and other conditions to develop systems of DBS which constantly sense an individual s underlying electrical activity and modulate the stimulation in an individually responsive manner. It is hoped that this will improve the effectiveness of treatment and reduce the side effects.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Wellcome Trust PhD Programme for Clinicians at the University of Dundee: 'Signalling pathway of Fbxo7 and its role in Hereditary Parkinsonism'.
Funder: Wellcome Trust

Abstract: Parkinson Disease (PD) is the second most common neurodegenerative disorder after Alzheimer Disease with significant burdens on individuals, their families, and on society. The discovery that PD follows Mendelian inheritance patterns in some families has led to the identification of PD associated genes. As sporadic and monogenetic Parkinsonism share important neuropathological and clinical features, notably the susceptibility of dopaminergic neurons in the substantia nigra to cell damage, insight into the function of disease causing gene mutations is expected to promote our understanding of key regulatory pathways involved in PD neurodegeneration. Mutations in the Fbxo7 gene have recently been linked to a complex, young-onset Parkinsonian syndrome. Little is known about the physiological role of the Fbxo7 protein or how mutations results in PD-associated neurodegeneration. The aim of my research project is to elucidate the signal transduction pathway of Fbxo7 utilizing standard and human-derived, patient-specific cell lines, but also by generating a new mouse model with human disease-associated knock in and conditional knock-out mutations of the Fbxo7 gene. It is hoped that the findings of the proposed project contribute to a better understanding of PD pathogenesis, the development of new treatment options and possibly the availability of a valid PD mouse model.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neurotrophin, Toll and Trk-like functional relationships in the Drosophila central nervous system.
Funder: Wellcome Trust

Abstract: The neurotrophin (NT) proteins are important for nervous system structure and function, and abnormalities in them cause brain diseases, e.g. neurodegeneration and psychiatric disorders. The Toll-like receptors (TLRs) underlie innate immunity, and defects result in diseases including infection and kidney disease. Although NTs and TLRs have largely been considered separately, there are possible overlaps as TLRs function in the nervous system and NTs are involved in immunity. We recently disco vered NTs in the fruit-fly Drosophila, a powerful model organism for investigating how genes function. Drosophila is used to model brain diseases, e.g. Alzheimer s and schizophrenia. We aim to discover how Drosophila NTs (DNTs) implement their functions in the brain. We suspect that DNTs activate evolutionarily modified forms of well-known NT receptors, and also Toll-like receptors, highlighting an interaction between these previously unlinked systems We will test this further in Drosophila. T his will reveal similarities and differences between the fruit-fly and human brains, and potentially an important evolutionarily conserved molecular mechanism. Working out the DNT receptor repertoire and what Tolls do in the CNS is essential in the use of Drosophila to understand the brain, to understand the links between the immune and nervous systems, and to model human brain disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Exploring the link between extrasynaptic GABA-A receptors and behaviour.
Funder: Wellcome Trust

Abstract: Sleep is one of the most powerful physiological drivers of behaviour and it clearly provides an essential biological need. We are interested in how natural sleep is regulated and why disturbances in sleep are a feature of many neurological disorders. This proposal concentrates on three brain regions that are involved in sleep: the thalamus, neocortex and striatum. We wish to examine how a novel population of neurotransmitter receptors expressed in these important brain regions can participate in the regulation of sleep. Disturbance in the function of these receptors has been associated with a number of neurological disorders, including epilepsy, depression and schizophrenia, but the function of these receptors is only beginning to be understood, and little is known about their role in the regulation of sleep. We will make use of novel molecular genetics to remove these receptors selectively from neurons within the thalamus, neocortex and striatum. We will then monitor the excitability of single neurons to establish the success of this technique before examining how sleep is altered at the level of global brain activity and whole-animal behaviour.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Molecular mechanisms of cranial motor nucleus formation.
Funder: Wellcome Trust

Abstract: The wiring of the human nervous system depends on around a hundred billion precise connections. Many nerve cells of a similar type cluster together in groups known as nuclei ('nucleogenesis'), and form specific connections with other nerve cells or with muscles. Although nuclei are a common feature of the nervous system, little is known of how or why they form. We will study the molecular mechanisms that underlie nucleogenesis among the motor neurons of the brainstem, which control the muscle s of the head and neck. For example, motor neurons which control facial muscles and eye muscles develop in the same region of the brainstem, but cluster differentially. We will focus on roles of the key family of cadherin cell adhesion molecules, and the possibility that they in turn are controlled by signals relayed by the fibroblast growth factors. As well as studying these detailed mechanisms, we will use perturbations of motor nucleus formation to determine the consequences. In this way we will discover whether neurons require to cluster within a nucleus in order to connect with the correct muscles, form synapses and produce patterns of electrical activity which are crucial for neural function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: G protein coupled receptor-dependent regulation of the exocytotic machinery.
Funder: Wellcome Trust

Abstract: All cells, including the neurones which mediate the functions of the nervous system, have on their surfaces specialized proteins, known as receptors, which sense the environment around them and detect the presence of chemical messengers sent from other cells. Binding of specific chemicals to the receptors, causes them to change their shape so that other proteins on the inside of the cell can now associate with them, interpret the message, and bring about a change in the cells function. The mo st common type of receptor belongs to a group known as the G protein-coupled receptor (GPCR) family. There are over 1000 different types of GPCRs in mammals regulating such diverse processes as emotions, memory and pain. Drugs targeting these receptors increase or decrease the activity of malfunctioning cells; over 40% of drugs work at GPCRs to alleviate the symptoms of disease. Our aim is to understand how GPCRs regulate the secretion of chemical messengers from neurones and to define the ro le of specific proteins in this process. Here we examine GPCRs that increase secretion of chemical messengers from neurones. The results will increase understanding of the therapeutic potential and possible side-effects of drugs acting at this class of receptor.


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