NIHRDataInsights/HRCSData huggingface dataset:
Title: Zebrafish central facility at KCL.
Funder: Wellcome Trust

Abstract: Although the human genome is now well characterised, the function of the majority its genes is still a mystery. A successful way to understand gene function is to manipulate these genes in animal models such as mouse, zebrafish or even fruitfly. KCL has seen an exponential growth of its research community using the zebrafish to study the development of the nervous system and the mechanism of neurological diseases. For these studies, it is essential to maintain large numbers of normal, mutant an d transgenic fish in very high quality aquaria. In the last year, the KCL facility is no longer covering the needs of the researchers. The facility has been operating at full capacity, preventing users from hosting new transgenic and mutant lines required for the progress of their research. Moreover, it has developed irreversible aging problems that will undoubtedly lead to severe restriction in the maintenance of our resources, with disastrous impact on research, if a new aquarium system is not installed in the near future. The purpose of this application is therefore to provide funds for building a new more effective and bigger facility, essential to ascertain the outstanding research contribution of 19 research teams at KCL.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: NEUROLOGICAL
Title: Cell and molecular functions of regulated heparan sulphate structure in the developing corpus callosum.
Funder: Wellcome Trust

Abstract: The function of our brains depends on connections between nerve cells formed by fine cellular extensions called axons. A little like us using a map to navigate, axons respond to signals from their environment to tell them which way to go. These signals are chemicals which attract or repel axons and guide them along the correct path and are identified by receptors on the surface of the axon which cause the axon to turn one way or the other. This process can go awry if special sugars or glycoprot ein sidechains found on the surface of cells are not constructed properly. We do not yet know why problems with the structure of certain glycoprotein sidechains give rise to problems in the axon s ability to navigate appropriately to their targets; the experiments in this proposal aim to find out. To investigate this question we will disrupt the formation of particular glycoprotein sidechains and see how this affects the ability of axons to find their targets. In the future we may be able to us e our knowledge of the normal processes involved in guidance of axons to repair axons lost either by disease or injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Pain intensity, pain location and pain modulation: a combined neurophysiological and psychophysical approach.
Funder: Wellcome Trust

Abstract: We experience pain because of the activation of special neurons ( nociceptors ) in our peripheral nerves. These neurons send signals to specific areas of our brain (called the pain matrix ) that generates the sensation of pain. This project investigates how neural activity in the pain matrix produces the subjective experience of pain. The most important qualities of bodily pain are its intensity and its location: how much pain, and where? We will use novel, improved methods for generat ing precisely-controlled heat stimuli to elicit pain sensations, and for reporting subjective experience of pain. These improvements allow us to understand how intensity and location of pain are coded in the brain. We propose 9 experiments delivering moderate heat pain to healthy volunteers. First, we investigate how precisely pain is localised on the body ( pain acuity ). Surprisingly, pain can show the same spatial precision as touch, suggesting strong interactions between these two sens es. Second, we identify the brain processes that most closely relate to experienced pain intensity. Finally, we investigate how touch can reduce pain intensity, as when we grip ourselves tightly after a wound. The results will provide missing knowledge allowing better understanding of key pain processes, suggesting more effective treatments of clinical pain.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: Integrated reflex control.
Funder: Wellcome Trust

Abstract: We take it for granted that we can run and not fall, but also perform voluntary movements that temporarily throw us off balance, like diving after a football. It is well understood of how inner-loop reflexes help up to maintain balance and the execution of voluntary movements is also well-studied. But how the brain coordinates these two often contradicting tasks is one of the big unsolved questions in neuroscience. When our brain tells our muscles to dive so we can catch a football, how does the nervous system modify the inner-loop reflexes and thus allows us to do so? We can study this in hawk moths. Like hummingbirds, these moths feed on nectar while hovering steadily in front of flowers. Similar to what our nervous system does when we play football; the moth combines inner-loop reflexes with voluntary manoeuvres. We already know individual nerve cells supporting stable flight and also those controlling distance to the flower. We can monitor changes in the electrical signals of those cells and relate them to the behaviour of the moth in the laboratory. Data from these experiments will reveal how inner-loop reflexes and voluntary movements coordinated without being in conflict with each other.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: LRRK2 modulation of Wnt signalling cascades in Parkinson's disease.
Funder: Wellcome Trust

Abstract: The symptoms of Parkinson's disease, such as tremor, muscle stiffness and slowing of movement, result from progressive neuronal death in multiple brain areas, leading to insufficient formation of the neurotransmitter dopamine. While these symptoms can be treated for a time with dopamine replacement therapies, there is currently no known cure. Mutations in the gene for LRRK2 are the most frequent known cause of Parkinson's disease. In addition to being a protein kinase, we have found that LRRK2 signals to cellular pathways using dishevelled' proteins. These normally bindto a part of LRRK2 that has GTPase activity and are affected by mutations in LRRK2 that cause Parkinson's disease.We have now uncovered additional evidence that LRRK2 uses these dishevelled proteins to activate cellular signalling cascades normally activated by binding of proteins called Wnts to Frizzled receptors at the cell membrane. Our new project aims to understand the role of LRRK2 in Wnt signalling pathways using modern molecular, biochemistry and cell culture techniques and two animal models that have defective Wnt signalling or enhanced LRRK2 activity. Our goal is to understand how defects in LRRK2 cause Parkinson's disease, providing key information that underpins the development of new drug treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Astroglial control of vital neural networks.
Funder: Wellcome Trust

Abstract: Interacting networks of brain cells called neurones - continually adjust our breathing and activity of the heart and blood vessels to meet the physical and behavioural demands of the body. The brain also contains astrocytes - a group of brain cells known as glia (which means glue in Greek). Glial cells are the most abundant cells in the human brain outnumbering neurons by a factor of ten to one. Until recently, glial cells have been thought to merely provide neurones with structural and nu tritional support. However, new experiments suggest that astrocytes are actively involved in brain information processing and control of complex behaviours. This project is designed to investigate the fundamental principles underlying glial influences over brain networks controlling breathing and cardiovascular activity. The results of the proposed research are expected to contribute towards our understanding of the fundamental principles of brain organization and function and also help to revea l causes of devastating conditions associated with respiratory failure (e.g. sudden infant death syndrome) and alterations in brain control mechanisms contributing to the development of diseases like hypertension and heart failure.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Exploring the roles of autophagy in the nervous system.
Funder: Wellcome Trust

Abstract: Intracellular protein misfolding/aggregation characterises many late-onset neurodegenerative diseases, including Alzheimer s disease, Parkinson s disease, tauopathies, and Huntington s disease (HD)). The mutations causing HD and many related diseases confer novel toxic functions on the specific protein. Thus, it is important to understand the factors regulating the levels of these proteins. (Macro) autophagy clears long-lived proteins and organelles by forming autophagosomes that engulf p ortions of cytoplasm. Autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Autophagy regulates the levels of intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases, including HD. Autophagy upregulation may attenuate diseases like HD, and possibly tuberculosis. Autophagy inhibition slows growth of existing tumors, and may also contribute to pathology in various neurodegenerative diseases. I aim to: Discover novel autophagy-modulating dr ugs/pathways and test their clinical relevance in models of neurodegenerative diseases, tuberculosis and cancer. Test if there are beneficial/deleterious effects of constitutive autophagy upregulation in vertebrates. Develop methods to infer autophagic flux in vivo. Understand how autophagy compromise causes pathology. Identify novel autophagy-regulating mechanisms and investigate possible disease relevance. These studies will help the understanding of the relationship betwee n autophagy, normal physiology and disease, and will provide proof-of-principle for autophagy-modulating strategies as therapies for a range of conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Autophagy in health and disease.
Funder: Wellcome Trust

Abstract: Many brain diseases, like Alzheimer s disease, Parkinson s disease, tauopathies, and Huntington s disease (HD) develop clumps of protein inside nerve cells. The mutations causing HD and many related diseases change the normal protein into a toxin. Thus, we need to understand the factors regulating the levels of these proteins. (Macro) autophagy mediates the removal of long-lived proteins and regulates the levels of intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseas es, including HD. Increasing autophagy with various drugs can slow the onset of diseases like HD in animal models, and there are data in cell systems suggest potential in tuberculosis. Autophagy inhibition slows growth of existing cancers, and may contribute to certain neurodegenerative diseases. I aim to: Discover novel autophagy-modulating drugs/pathways and test their clinical relevance in models of neurodegenerative diseases, tuberculosis and cancer. Test if there are beneficial/d eleterious effects of continuous autophagy upregulation in vertebrates. Develop methods to measure rates of autophagy in whole animals. Understand how autophagy compromise causes neurodegenerative diseases. Identify novel autophagy-regulating mechanisms and investigate possible disease relevance. These studies will help the understanding of the relationship between autophagy, health and disease, and will provide proof-of-principle for autophagy-modulating strategies as therapies for a range of conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The integration of activation and inhibition signals in natural killer cells in autoimmunity.
Funder: Wellcome Trust

Abstract: Recent work from the two host labs has covered complementary aspects of natural killer cell activation. The Altmann lab showed that programmes of NK cell activation may be protective in the context of multiple sclerosis. The Long lab has developed molecular and cellular reagents for probing signal transduction in NK cell activation. There is a lack of clarity as to the mechanism of NK cell activation in the context of MS. I would like to define NK receptor?ligand interactions and their downstream consequences in MS. Such information could illuminate the mechanism of protection provided by NK cells in disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Homeostatic plasticity: from synapses to the axon initial segment.
Funder: Wellcome Trust

Abstract: Our bodies tightly regulate many aspects of its inner physiology, such as temperature, blood pressure and glucose levels. This process, known as homeostasis, serves to keep certain key physiological events constant in the face of a continuously changing environment. Neurons in the brain are no different. It is now known that the electrical activity of neurons also needs to be tightly regulated to avoid reaching extreme levels. Without these safeguards, the brain would be at the mercy of ongoing fluctuations in neuronal activity which could, at its extreme, result in the high levels of abnormal brain activity that cause epilepsy. As a result, neurons have developed many homeostatic mechanisms that help keep activity within a normal operating range. Despite the importance of neuronal homeostasis in stabilizing brain function, little is known about the mechanisms that control it, the site in the neuron at which it takes place nor even the levels of activity a neuron senses as abnormal. He re, we aim to tackle these questions by using techniques that provide fine control of the electrical activity of neurons by means of light. This non-invasive approach will help study neuronal homeostasis and could uncover potential new targets for epilepsy treatment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Synaptic and neuronal determinants of network function: Application of new optical and computational tools.
Funder: Wellcome Trust

Abstract: Brains are able to control bodies with amazing speed and precision. For example, the brains of tennis players coordinate their muscles rapidly and can adapt movements to fast incoming sensory information about the motion of the ball. Understanding how such information is represented in electrical signals flowing through complex networks of cells (neurons) in the brain, is one of the most exciting and challenging problems in science. We do not know how the electrical properties of neurons or the synaptic connections they make with other neurons in a network helps the brain make use of these electrical signals. We do know that connected neurons can generate oscillations (brain waves) in network activity, but their precise role is not clear. This knowledge is important because it is a prerequisite for understanding what goes wrong during neurological disorders. I will tackle this complex problem by applying several powerful new techniques, including a new type of 3D microscope that can r apidly monitor signals within neurons and across networks of neurons, and state of the art computer models of neuronal networks. I will focus on the cerebellar cortex which provides coordinated movement, because we know much about its structure.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Neuronal integration in sensory cortex: New paths to discovery
Funder: Wellcome Trust

Abstract: The cortex is known to process images and sounds through the activity of neurons in visual and auditory areas. However, little is known about how cortical populations integrate multiple sensory streams and modalities into coherent pattern, and how sensory-driven activity interacts with non-sensory, endogenous patterns of activity. These patterns may provide the context neededto interpret sensory signals and act upon them. We seek a unified view of how the cortex integrates multiple external and endogenous signals into the activity of neuronal populations. To this end, we will address a series of related questions within a common experimental framework: (1) What is the structure of population activity in sensory areas of the awake cortex? (2) What are the rules of interaction of multiple signals in awake cortex? (3) Howdoes the structure of population responses change with cortical state? (4) Howdoes cortical population activity relate to sensory-driven behavior? (5) What mechanisms control brain state and the structure of population activity? By answering these questions we seek to uncover fundamental laws that predict thethe population activity from sensory input and internal state, and that predict perceptual choice from population activity, and to provide insight into the underlying circuits and mechanisms


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Integration of internal and external signals in sensory cortex.
Funder: Wellcome Trust

Abstract: The cortex is known to process images and sounds through the activity of neurons in visual and auditory areas. However, little is known about how cortical populations integrate multiple sensory streams and modalities into coherent pattern, and how sensory-driven activity interacts with non-sensory, endogenous patterns of activity. These patterns may provide the context needed to interpret sensory signals and act upon them. We seek a unified view of how the cortex integrates multiple external and endogenous signals into the activity of neuronal populations. To this end, we will address a series of related questions within a common experimental framework: (1) What is the structure of population activity in sensory areas of the awake cortex? (2) What are the rules of interaction of multiple signals in awake cortex? (3) How does the structure of population responses change with cortical state? (4) How does cortical population activity relate to sensory-driven behavior? (5) What mechanisms control brain state and the structure of population activity? By answering these questions we seek to uncover fundamental laws that predict the population activity from sensory input and internal state, and that predict perceptual choice from population activity, and to provide insight into the underlying circuits and mechanisms


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Injury and repair of the peripheral nervous system: The role of Neuregulin-erbB signalling.
Funder: Wellcome Trust

Abstract: Injury to the peripheral nerves results in weakness, numbness and can lead to chronic pain. Although a degree of recovery can occur following injury this is often incomplete resulting in long term disability. Communication between the different cell types within the nerve for instance axons (which can be likened to cables carrying electrical impulses) and Schwann cells (which insulate axons) is extremely important in co-ordinating the repair process. Neuregulin-1 (NRG1) is a protein which exists in a number of different forms which are present on the surface of, and can be released from, damaged axons. This protein has a well- known role in the development of nerves; however up to the current time its function in the adult has been difficult tostudy. I will use genetic techniques to modulate the level of different forms of NRG1 on damaged axons Iwill investigate whether NRG1 provides a signal between different cell types in order to help repair damaged nerves. I will also test whether some forms of NRG1 may be unhelpful contributing to the development of chronic pain. The ultimate goal of this project is to find potential means to promote recovery following nerve injury and restore normal function.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Imaging pain in the developing human brain
Funder: Wellcome Trust

Abstract: Infant pain is a major clinical problem. Not only does it reduce the quality of life for hospitalised infants but it can also have long-term consequences. The goal of this researchis to improve the clinical care provided to some of the most vulnerable members of society. As babies are unable to tell us when they experience pain, it is difficult to measure their pain effectively and to make sure that they are receiving the appropriate level of pain relief. Using a newmethods, that I have developed, to look at the pain activity in the infant brain, I would liketo answer some specific scientific and clinical questions: (i) When, during early development, does the human brain discriminate pain, touch and other sensory experiences? (ii) Can brain imaging be used to identify the deeper structures of the brain that are activated when a baby is in pain? (iii) How is infant pain behaviour related to pain-specific brain activity andspinal cord activity? (iv) Does morphine relieve pain caused by medical interventions, such as taking a blood sample?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Exploring functional and structural plasticity of visual pathways following hemianopia in stroke.
Funder: Wellcome Trust

Abstract: Every year sees approximately 150,000 new cases of stroke in the UK, leaving at least one in six patients blind in half of their visual field due to damage at the back of the brain. This is extremely debilitating, with patients unable to drive or often return to work. Whilst damage to other parts of the brain can undergo complete recovery with early and targeted rehabilitation, this condition is poorly understood with no effective treatment. In fact, considerable evidence suggests that whilst conventional testing shows patients to be blind, some information about the visual world seems to get through and influence behaviour. This can occur even though the individual is often completely unaware that they see anything at all! This is unconscious processing, and the phenomenon is called 'blindsight'. Blindsight is believed to represent changes to connections within the brain, so-called plasticity, and is now thought to exist in most stroke patients. Understanding remaining visual fu nction in these 'blind' patients is important for guiding rehabilitative therapies. I will use non-invasive brain-imaging technology to investigate whether and how the visual brain undergoes structural and functional changes after stroke. I will then evaluate whether further changes can be induced through targeted rehabilitation.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL