NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding variability in systems pharmacology with application to drug target identification
Funder: Wellcome Trust

Abstract: There is currently a big gap between understanding the molecular mechanisms ofbiological networks, identifying drug targets and predicting clinical outcomes of drug treatments in a heterogeneous population of patients. The goal of this project is to narrow this gap by developing a framework that combines mechanistic systems modelling, drug pharmacokinetics and patient variability in a unified fashion. This framework will enable us to make progress in understanding healthy and diseased network physiology, guide us to select optimal drug interventions andquantitatively predict the success of drug therapies on variable patient subpopulations. Specifically, I will develop a quantitative systems pharmacology (QSP) model of a nerve growth factor (NGF) signalling pathway using clinical and molecular data. I will extend the existing model to capture variability in the biological pathway as well as variability between and within individual patients. The model will be used to identify robust drugtargets and to guide aspects of quantitative drug discovery and development for treating paindisorders.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Dissecting alpha-synuclein pathology in Drosophila models of Parkinson's Disease: aids to understanding idiopathic Parkinson's Disease.
Funder: Wellcome Trust

Abstract: My research project will use Drosophila melanogaster to model novel mutations in the GBA, PANK2 and PLA2G6 genes known to cause parkinsonism and ?-synuclein pathology in humans, in order to identify common pathogenic pathways in idiopathic PD. This will involve knockout of the GBA, PANK2 and PLA2G6 genes and also expression of PD-associated mutant forms of these genes in Drosophila neural tissue, both in the presence and absence of ?-synuclein expression. These fly models will be characterised, including the effect on longevity, locomotor ability and neuronal viability. I will then study the role of ceramide metabolism in these PD models by comparing the temporo-spatial relationships between these neurotoxic phenotypes and abnormalities in ceramide metabolism. Furthermore I will identify links between ceramide levels and downstream effectors such as mitochondrial, autophagy-lysosomal and proteasomal pathways. In addition, I will determine how loss of function of GBA, PANK2 and PLA2G6 gene products affect the onset and severity of ?-synuclein pathology in flies co-expressing ?- synuclein. In particular, I am interested to determine how these mutations differentially affect the soluble and insoluble pools of ?-synuclein in fly brains. Finally, I will use these fly models as a platform of drug discovery to screen compounds that are predicted to interfere and protect against neurodegeneration by altering ceramide and autophagy pathways.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Advancing a transformative health technology: smartphone-based rapid, non-invasive telemonitoring and symptom prognosis for progressive neurological disorders
Funder: Wellcome Trust

Abstract: Previously, the applicant produced algorithms to predict the symptoms of Parkinson.s disease using voice recordings. By bringing similar algorithms to the smartphone (iPhone/Android), with close to 50% US/UK adoption, the ability to non-invasively, rapidly, and cheaply, monitor the symptoms of progressive neurological disorders could enable some radical reductions in inefficiencies in healthcare provision and research. This proposal will createa practical set of algorithms, implemented in software on smartphones, to quantify the symptom severity of several progressive neurological disorders (e.g. Parkinson.s, ALS and multiplesclerosis), with at most one day between measurements. Some of the algorithms will analyse sensors such as microphones, accelerometers, and touch screens, and convert it into clinically-relevant outcomes on standardized clinical scales. Other algorithms will make predictions of future symptom severity. The results of this research will have significant impact across a range of applications, including: speeding up clinical trials by allowing remote follow-up of participants. responses to new treatments; and easing logistical difficulties for patients who can reduce the need for clinical visits for routine checkups. It will result in a very large database (500 . 3,000 participants) of clinical data of unprecedented detail on the progression of several, serious neurological disorders.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Studying neurogenesis through developmental time.
Funder: Wellcome Trust

Abstract: The nervous system is derived from progenitor cells during the formation of the embryo. Progenitor cells are defined by their ability to divide; as they divide some of their progeny, and sometime all, become specialised neurons and glia which no longer divide, but produce proteins needed for the function of neurons and their support. As the embryo develops, the pool of progenitor cells gradually gets depleted in a controlled manner. A small number of progenitors persist into adulthood, the so -called adult stem cells, and these may contribute to generation of new neurons, where they are needed, and repair. This proposal is concerned with understanding the mechanisms that inhibit progenitor cells from becoming specialised cells prematurely during the formation of the embryo. We call this progenitor maintenance. There is more than one mechanism involved in progenitor maintenance, and these may operate at different times and locations in the nervous system. In two of our aims we prop ose experiments that will lead to a better understanding of two such mechanisms In the third aim, we follow the destination of early progenitors, to find out whether the long-lasting ones have a special origin in the embryo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Mechanisms of Schwann cell myelination and dedifferentiation: relevance to nerve repair and pathology.
Funder: Wellcome Trust

Abstract: Peripheral nerves consist of two principal cellular components, nerve fibres (axons), and their supporting cells, Schwann cells. During nerve development, Schwann cells become highly specialized and make protective myelin sheaths around large axons. Axonal signals control this process and disturbances in myelin maintenance lead to disorders of movement and sensation (demyelinating neuropathies). Remarkably, the process of myelination is reversible. After nerve injury, Schwann cells dediffere ntiate, lose myelin and reacquire properties resembling those of immature Schwann cells before myelination. This process is vital to nerve repair because these dedifferentiated Schwann cells provide territories through which injured axons regrow, reacquire myelin sheaths and reconnect with their targets, such as muscle, to lead to restoration of function. Schwann cell dedifferentiation requires the action of molecules that oppose the signals that control myelination. We refer to these as ne gative regulators of myelination. We find that two of them, c-Jun and Notch, play vital roles in Schwann cell dedifferentiation and nerve repair, and that they likely play a role in the demyelination seen in demyelinating neuropathies. We aim to understand how these molecules work in injured and diseased nerves, with a view to improving regeneration of nerve fibres and controlling demyelination in peripheral nerve diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Nitric Oxide signalling and the modulation of mammalian spinal motor networks
Funder: Wellcome Trust

Abstract: For almost a century we have known that the mammalian spinal cord contains networks of neurons which control locomotion, but our understanding of these networks is still very limited. In order to design new treatments for injuries or diseases affecting spinal cord functions we must first understand how the healthy spinal cord controls movement. It is therefore of critical importance that we undertake basic research with the goal of determining how neurons in the spinal cord come together to fo rm a control centre for locomotion. The proposed study aims to provide some of this important knowledge by investigating how a particular signalling molecule, nitric oxide (NO), is involved in the communication between spinal neurons and how this may help to control locomotion. We will answer these questions by using state-of-the-art anatomical and physiological techniques which allow us to visualise and record the activity of single neurons in isolated pieces of mouse spinal cord tissue which can elicit locomotor activity in a dish . We expect our findings to significantly advance knowledge of spinal motor networks and to improve understanding of NO-mediated signalling throughout the brain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Genetic dissection of intercellular signalling during development of the mammalian cerebellum.
Funder: Wellcome Trust

Abstract: The cerebellum is an important part of the central nervous system and developmental disorders of this region of the brain are associated with uncoordinated movements (ataxia), autism, schizophrenia, dyslexia and the most prevalent of all childhood cancers, medulloblastoma. Uncovering the basic mechanisms that control development of the cerebellum is therefore important to understand the basis of these disorders. As similar mechanisms also control the development of other brain regions, our knowl edge on cerebellar development can also be applied to understand the development of these areas better. Glial cells are important for guiding the migration of neurons to their correct positions in the developing brain. Recent experiments in our laboratory have shown that glia in the cerebellum may also have important roles in regulating the proliferation of granule cell precursors, which produce the most numerous type of neuron in the brain and are the cells that are transformed in medulloblasto ma. We propose experiments to understand how these glia and other cell types use particular signalling molecules to communicate with each other in the developing cerebellum. Our experiments will demonstrate the importance of maintaining the appropriate levels of signalling in cells and how disrupting these normal levels affect cerebellar development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Determinants of oligodendrocyte cell fate in development and disease.
Funder: Wellcome Trust

Abstract: For our brain to work, fast electrical communication between nerve cells is essential. This is achieved by insulating the nerves with a fatty substance called myelin. In diseases like multiple sclerosis, spinal cord injury and stroke, myelin is lost, while in cerebral palsy myelin fails to develop. Lack of myelin causes physical and mental disability. Myelin is provided by cells called oligodendrocytes, which develop from oligodendrocyte precursor cells (OPCs). In the adult, OPCs can repair myelin, but this repair often fails for reasons currently unknown. OPCs can also develop into other types of brain cell, including nerve cells, but it is not known what controls this choice of cell identity. I will study how OPCs generate myelin during development and in disease. I will investigate how signals in the cells environment interact with the properties of the OPCs to instruct them to migrate, generate myelin-making oligodendrocytes, or develop into other brain cells. The long -term aim of this work is to understand how OPCs decide to become myelinating cells, how we can influence them to repair myelin in disease, and possibly how to make them generate nerve cells that could be used to treat other types of brain disorder.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Profiling dementias using complex sound: from symptoms to brain networks.
Funder: Wellcome Trust

Abstract: The common dementia diseases have devastating human and socio-economic impact on our ageing society. Many patients with dementia have difficulty understanding speech and other sounds in daily life: this is a major source of disability, and may also hold clues to the nature of particular dementia diseases and degenerative brain disease more generally. Despite recent advances in genetics and pathology, we still do not understand why such symptoms develop. Here I propose a new study using complex s ounds (speech, music, environmental noises) to investigate the brain processes that malfunction in dementia. The brain changes associated with listening to a range of different sounds will be compared in volunteer patients with dementia, people at-risk of familial dementia, and healthy older volunteers using specialised MRI brain scanning, psychological and hearing tests. Because sound processing engages many brain areas, this approach promises to identify changes at the level of brain networks rather than single areas, and therefore to arrive at a deeper understanding of how symptoms arise in dementia. This information could be used in future to achieve early diagnosis of dementia, to distinguish different dementia diseases, and to help develop and assess treatments for sound-related symptoms and ultimately the dementia disease itself.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Foxg1-dependent regulatory network controlling telencephalic boundary and neuronal fate specification.
Funder: Wellcome Trust

Abstract: Human brain disorders are mostly caused by errors made in the formation of the forebrain during the development of the foetus. To prevent or cure these dreadful malformations, we need to understand how the forebrain is developing and how cells are organizing in the forming brain to make functional circuits. One of the genes found to be involved in brain disorders is Foxg1. The consequences of Foxg1 mis-function range from severe mental retardation to autism. Foxg1 is necessary for our brain to m ake the right types and number of neurons (one of the key cell type in our brain) in our cerebral hemispheres. The protein is also needed to make these neurons at the right place inside the forebrain. This proposal aims to find out how this molecule is achieving these crucial tasks.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Epigenetic control of reprogramming of astrocyte into neurons.
Funder: Wellcome Trust

Abstract: Many diseases of the brain, such as Alzheimer s disease or stroke, result in a damaging loss of nerve cells, and there is currently no available treatment to reverse such losses. A new strategy that is envisaged to treat these diseases is to convert other kinds of cells into nerve cells to repair the damages in brain tissue. We have previously shown that a type of cells that is present in abundance in the brain and serves to support and nourish nerve cells, called astrocytes, can be cultivated i n the laboratory and converted partially into neurons. The procedure involves the introduction in astrocytes of a protein called Neurog2, which is normally involved in the generation of nerve cells in the embryo. The procedure is however not yet satisfactory as the converted astrocytes lack many features of nerve cells and are not functional. Our goal with this project is firstly to understand why the protein Neurog2 is not fully functional in astrocytes, and secondly to use this knowledge to im prove Neurog2 activity and boost the conversion of astrocytes into functional nerve cells.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Characterising the application of non-invasive brain stimulation in the neurorehabilitation of dysphagia after stroke.
Funder: Wellcome Trust

Abstract: Each year, thousands of people in the UK suffer the distressing problem of being unable to swallow after a stroke which increases 3 fold their chance of premature death. Many of these patients have to be fed by a tube directly into the stomach, while waiting for natural recovery to slowly occur over weeks to months, if at all and for some tube feeding becomes a permanent requirement. Given this appalling situation a better understanding of how the brain responds to differing forms of stimulation would clearly help our ability to deliver more effective therapies for swallowing problems after stroke. This proposal will seek to identify new approaches to enhance and accelerate natural recovery processes after brain injury, focussing on swallowing. In order to achieve this goal, we plan to assess how brain stimulation alters both brain properties and swallowing function in healthy subjects using new brain imaging technologies such as transcranial magnetic stimulation. We will then go on to study stroke patients with swallowing problems to determine the best parameters for stimulation and recovery. Ultimately, this work will lead to the development of new treatments that can help accelerate the recovery process for brain damaged patients.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL
Title: Mechanism of physiological thalamocortical rhythms
Funder: Wellcome Trust

Abstract: Each behavioural state (i.e. attentive, relaxed, sleeping) is characterized by a unique brain electrical activity. These behavioural state-dependent brain outputs result from the activity of specialized cells (called neurons) not only in the cortex (the outer-most region of the brain) but also in deeper brain areas. One of these regions (called the thalamus) exerts a powerful modulation of, and in some cases does indeed drive, the electrical activity of cortical neurons. This proposal aims at in vestigating the mechanisms that control the electrical output of thalamic neurons. In particular, we will study how the interactions of electrical signals between large populations of cortical and thalamic neurons lead to the expression of brain waves that are characteristics of relaxed wakefulness and different stages of sleep, and will investigate how biochemical modifications (i.e. changes of calcium concentration) in the elongated processes (called dendrites) of individual thalamic neurons a ffect the transfer of electrical signals between the reciprocal connections that link thalamus and cortex. By furthering our knowledge of the basic operations occurring in the brain under normal conditions, this study will contribute to the potential development of novel therapeutic interventions in sleep disorders and other diseases that affect thalamic and cortical neurons.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Spine Specific Targeting of Ion Channels in Striatal Neurons.
Funder: Wellcome Trust

Abstract: Neurons in the brain communicate with each other at specialised contacts known as synapses. A single neuron typically receives thousands of synaptic inputs from other cells located across the brain. Different synaptic contacts carry unique functional information, but their properties are difficult to study in isolation. I propose to explore the precise location and functional organisation of different synapses onto neurons in an important area of the brain called the striatum. These neurons inte grate signals from many brain regions important for reward seeking, and their dysfunction is implicated in debilitating diseases like Parkinson's, schizophrenia and drug addiction. I will use genetic tools that allow me to selectively stimulate inputs from individual brain regions with light, and high-resolution microscopy to assess where these inputs connect with individual neurons. I will then use selective blocking drugs to assess which molecules are used for communication at different synaps es, and molecular techniques to determine the mechanisms that enable their specific targeting to synapses. These novel experiments will determine how neurons in the striatum respond to their many different inputs. More generally, they will provide a better understanding of how neurons in the brain are connected with each other and share information.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Molecular spatio-temporal dynamics of neuronal Sec-1 protein.
Funder: Wellcome Trust

Abstract: Exocytosis is the process of secretion from specialised cells. Mis-regulation of this process is central to many disease states, such as diabetes and epilepsy. The proteins involved in exocytosis are well known to science, but the location and timings of their actions inside cells remain unknown. This work aims to examine the types of interactions between 2 of these proteins, both absolutely essential for exocytosis. Our laboratory combines biochemistry with cutting edge microscopy techniques, w hich can visualise directly the sites of interaction between proteins inside living cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Regulation of self-renewal and differentiation in the Drosophila CNS.
Funder: Wellcome Trust

Abstract: One of the goals of research in neurobiology is the repair or regeneration of neurons after damage to the brain or spinal cord. Before we can understand how to repair the nervous system, we must first learn how the nervous system is put together. Of all the tissues and organs in the human body the nervous system is the most intricate and complex, consisting of billions of neurons. These neurons make precise connections with each other to form functional networks that transmit information at amaz ing speed over considerable distances. Neurons are produced by multipotent precursors called stem cells. Neural stem cells divide in a self-renewing manner, generating daughter cells that give rise to different types of neurons. We aim to identify the genes that direct the different behaviours of cells in the developing nervous system. What genes direct a neural stem cell to divide rather than become a neuron? What genes determine the type of neuron that is born? By identifying the genes tha t specify the characteristic behaviours of each cell type in the nervous system, it should become possible to manipulate stem cells to become neurons at will, or to induce neurons to regenerate.


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