NIHRDataInsights/HRCSData huggingface dataset:
Title: Measuring and modelling the dynamics of retinotopic map formation.
Funder: Wellcome Trust

Abstract: Connections are made between nerve cells of different parts of the brain as it develops. We have learnt an enormous amount about the various cues involved in setting up these connections. Most is known about the specific connection patterns between the eye and the visual areas of the brain. However, our knowledge is largely descriptive; we know what connections are formed but we do not know how. Computer models can provide powerful insights into how connections (or circuits) are formed, par ticularly when based on biological data, and can also guide the collection of biological data. We aim to establish a two-way interaction between modellers and experimentalists to: (i) optimise the collection of data on circuit formation; (ii) generate models that have biological credibility and predictive power. It is very likely that the same set of cues is used in the development of many brain circuits, although to different extents. Having a biologically-realistic model with predictive pow er will allow us to generalise our ideas to other circuits in the brain. It will also help us understand how the brain works when the full set of cues is unavailable. This will enable the treatment of developmental disorders and restoration of circuits following damage.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Award made to cover animal costs on Federica La Russa's 4-year PhD. DW 13.12.13
Funder: Wellcome Trust

Abstract: Chronic pain is prevalent and its clinical treatment remains limited. The London Pain Consortium (LPC) will advance knowledge of chronic pain mechanisms through internationally competitive research and provide multidisciplinary training of clinical and biomedical scientists to promote careers in neurobiology in general and pain studies in particular. In man and animals, we will: 1) identify molecular and genetic influences on pain processes; 2) study the integrative functions of these influenc es and their translation as therapeutic targets; 3) provide research and training resources for the wider scientific community.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Formation and Function of Insulin-producing Neurons in Drosophila.
Funder: Wellcome Trust

Abstract: Insulin and insulin-like growth factors are molecules that control sugar levels and tissue growth in many organisms Although they often have effects on the human body as a whole, they can also be secreted locally to affect specific tissues. However, this function is less understood. In order to treat diseases such as diabetes we need to understand how and why these molecules are made. Fruit flies are easier to study than higher animals, and the activity of their genes can be readily manipulat ed. Previous work has shown that, like humans, flies also have insulins. Some of these insulins are released into the circulation and regulate body size and sugar levels. However, we have identified a set of fly neurons that secrete a different insulin in the fly s gut. This is interesting because it suggests that, as in humans, fly insulins may also act locally. We will investigate what the function of this local insulin activity is, and we will try to identify the genes that make these neuron s produce insulin. Given that 60% of fly genes are conserved in humans, the genes we identify are likely to be important for insulin preduction in humans and may eventually help treat diabetes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Causes of focal epilepsy, particularly antenatal and perinatal insults associated with epilepsy in three different regions of Africa.
Funder: Wellcome Trust

Abstract: I plan to conduct cross sectional surveys in five demographic surveillance sites across sub-Saharan Africa, to identify cases of active convulsive epilepsy (ACE). This cohort will be used to determine the prevalence of ACE and the extent of the number of people not receiving treatment (treatmetn gap) in these sites, identify the causes (particularly parasitic diseases that could be prevented) and establish cohorts of people with epilepsy, from which the magnitude and causes of excess mortality a ssociated with epilepsy can be determined. In addition, a community based intervention will be tested through a randomised cluster trial in one of the sites, to reduce the treatment gap and improve the quality of life of people with epilepsy in this area.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: NEUROLOGICAL
Title: Molecular mechanisms of Hesx1 function in early forebrain development.
Funder: Wellcome Trust

Abstract: The proposed research will investigate the molecular mechanisms responsible for normal forebrain and pituitary gland formation in humans and mice. The forebrain includes the eyes and the cerebral hemispheres, and in humans is where cognition, memory, language and emotion reside. We will focus on the developmental control gene Hesx1, which is particularly interesting for two reasons. First, mutant mice with a deficiency in Hesx1, show profound forebrain defects. Second, in humans there is a link between mutations (genetic changes) in the HESX1 gene and some disorders, such as congenital hypopituitarism and septo-optic dysplasia (SOD). These are human conditions characterised by abnormalities in the pituitary gland and/or forebrain structures (eyes, optic nerves and some brain connections), which may lead to severe impairment of life, mental retardation, blindness or even death. Our research has linked Hesx1 to an important molecular pathway (called the Wnt pathway) that regulates basic cellular functions during development, but is able to cause disease when defective. Now we propose to investigate in detail how Hesx1 interacts with this and other pathways during development. The results obtained from the proposed research will lead to a deeper understanding of the mechanisms underlying congenital disorders associated with phenotypes in the forebrain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Genome-wide association studies in partial epilepsies.
Funder: Wellcome Trust

Abstract: Epilepsy, a common serious brain disease, affects ~450,000 people in the UK. Its consequences are pervasive for sufferers, yet epilepsy remains stigmatised and under-resourced. A recent All-Party Parliamentary Group report recognised that lives are being lost and millions of pounds wasted because of insufficient funding for care and research into epilepsy. In most cases, we don't even know why people have epilepsy, and although drugs are available that can control seizures in many patients, we clearly need to understand more about epilepsy so that we can better control and prevent seizures and the consequences of epilepsy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Patterning of sub-regions in the Drosophila brain.
Funder: Wellcome Trust

Abstract: The objective of this research is to understand how cells in the fly brain obtain their identity. This process involves the action of specific genes at different time points during development. Some of these genes are known but many still need to be discovered. I have identified a gene odd-skipped (odd) that may be involved in specifying the identity of a small group of cells, potentially involved in learning and memory. My data also suggest that the action of odd could be involved in specifying other areas of the brain. I will investigate how the action of odd specifies cells within the brain. I will do this by abolishing the action of odd and assess how the brain anatomy changes. I will activate odd in cells where it is not normally active to see if these cells will behave like cells that normally have active odd. I will address the function of the cells in learning and memory by silencing them and see what effect this has on the memory of the fly. Finally I will look for more novel genes that are involved in specifying other regions of the brain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Neurodegeneration and aging: roles for DNA single-strand break repair.
Funder: Wellcome Trust

Abstract: The SSBR proteins TDP1 and Aprataxin are mutated in two distinct neurological diseases; spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and ataxia oculomotor apraxia-1 (AOA1). The goal of this proposal is to (1) Characterise mechanisms of SSBR in primary neural cells using a combination of in vitro biochemical assays (employing synthetic oligonucleotide substrates) and cellular chromosomal DNA repair assays (employing the alkaline comet assays). I propose to define the intermediates that accumulate in neural cells that are defective in SSBR using biochemical approaches and to characterise novel factors in this pathway using yeast 2-hybrid and co-immunoprecipitation experiments. (2) Elucidate the impact of un-repaired SSBs on neural cell fate, with emphasis on transcriptional competence and survival of primary neural cells. (3) Evaluate the neuroprotective effect of SSBR in vivo, by measuring specific behavioural and physiological end points in wild type and SSBR-defective mouse model systems.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Axon navigation in the developing brain.
Funder: Wellcome Trust

Abstract: When an animal or a human develops, it must build a brain that is capable of and ready for guiding appropriate actions and learning about the world. To do this, nerve connections must be accurately formed, so that, for example, the eyes provide visual signals to the parts of the brain that are able to generate sense and action out of this visual information. I have had a long term interest in how the nerve fibers from the retina find their way to the correct parts of the brain during developme nt, and I am proposing to continue this work by following up a set of exciting new discoveries that we have recently made showing that the growing tips of nerve fibers respond to guidance cues by changing their constituent proteins. This allows these growing fibers to adjust their sensitivity to particular cues, without which they would make serious navigational errors. We are now in an excellent position to examine these processes and their role in nerve guidance in some detail and derive a r eal basic understanding of how this works.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Paranodal demyelination in chronic spinal cord compression.
Funder: Wellcome Trust

Abstract: Spinal cord compression is a common clinical problem in both humans and animals, and a frequent cause of paralysis and pain. Although treatment by surgery is often useful, some patients suffer a poor or unpredictable response. At present there is an incomplete understanding of the effect of long-term spinal cord compression on the health of cells in the spinal cord and no available information at all on the effects of removing compression. We have collected preliminary evidence that compress ion causes damage to the myelin sheaths that surround nerve fibres in the spinal cord. If these myelin sheaths are damaged nerve conduction fails, and affected nerve fibres may be more likely to be destroyed. In addition, alleviation of spinal cord compression may incite an additional wave of injury during the rapid restoration of blood flow, perhaps because the damaged myelin makes the nerve fibres more susceptible to this type of injury. The aim of this project is to examine these possi bilities in more detail: we will focus on the health of the nerve fibres and their myelin sheaths during both phases i.e. during the period in which the spinal cord is compressed and when the pressure is relieved.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The TNF superfamily in neuronal development.
Funder: Wellcome Trust

Abstract: The immense complexity of the nervous system results from the orchestrated growth of neural processes during development to establish an ordered network of connections that is modified throughout life as we acquire skills and lay down memories. For these reasons elucidating the mechanisms that control the growth and morphology of neural processes is important for understanding how the nervous system develops and is shaped by experience. Recent research has revealed that several members of a larg e family of proteins that have important functions in the immune system play an unexpected and prominent role in controlling the growth of neural processes during development. We will determine how extensively this family of proteins regulates the growth and morphology of neural processes by extending our studies to additional members of the family based on when and where the receptors that permit neurons to respond to these proteins are located. We will investigate if these proteins can guide p rocesses as well as stimulate or inhibit their growth and will elucidate the molecular chain of events that mediate their actions in neurons. In addition to studying cultured neurons, we will study genetically modified mice to clarify role of these proteins in the intact nervous system.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: TARP regulation of neuronal and glial calcium-permeable AMPARs in health and disease .
Funder: Wellcome Trust

Abstract: Glutamate is the most important excitatory neurotransmitter in the brain conveying signals between nerve cells by activating specific receptors that are present at their contact points (synapses). Malfunction of one type of glutamate receptor (AMPA receptor) plays a key role in several CNS diseases, including multiple sclerosis, brain tumor growth, motoneuron disease, stroke and epilepsy. Accordingly, there is an urgent need to determine the principles that govern AMPA receptor function at a c ellular and molecular level. Such information is vital if we are to understanding normal synaptic transmission, and to reveal approaches that may be used to modify and alleviate disease conditions. The properties of AMPA receptors are dictated by their constituent building blocks (subunits). The presence or absence of one of these the GluR2 subunit determines whether AMPA receptors enable calcium ions to enter nerve cells. This feature appears to be a crucial trigger in many CNS disorders . Recently, members of a new family of molecules (TARPs) have been discovered that affect the properties of AMPA receptors and their delivery to synapses. Our research is aimed at understanding, specifically, how TARPs control the function of calcium-permeable AMPA receptors.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Population coding of natural sounds in the mammalian auditory system.
Funder: Wellcome Trust

Abstract: There are a number of disconnects between the processing of natural sensory stimuli in the mammalian brain and the experimental approaches that are used to study its physiological properties. For example, the brain consists of billions of interconnected neurons that process information in parallel, but most experiments in sensory physiology are based on recordings from individual neurons. Furthermore, the artificial laboratory stimuli that are typically used in these experiments lack the complex statistical properties that are common in the natural environment. The consequences of these discrepancies are evident in the inability of current models to predict the responses of sensory neurons to natural stimuli, a prerequisite for the successful implementation of neural prosthetic devices. With the goal of bridging these disconnects, I have designed a series of research projects which utilize recent technological advances for recording the simultaneous responses of neuronal populations to natural stimuli. The results of this research will provide fundamental information about the processing of natural sounds in the midbrain, a major integrative center in the central auditory system which has recently been identified as a promising site for prosthetic implants in patients with neural deafness.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Wellbeing, consciousness and moral decision-making: key concepts in biomedical ethics.
Funder: Wellcome Trust

Abstract: Radical advances in biotechnology and the neurosciences are raising unprecedented ethical challenges. Employing an approach to biomedical ethics that tightly integrates rigorous philosophy and close collaboration with scientists, clinicians, and other disciplines, and building on my prior research, I will make significant contributions to three key issues: (1) I shall write a monograph offering a revisionary understanding of the interrelated concepts of wellbeing, impairment, disability a nd enhancement, an account that will be then used to address controversial questions in the ethics of genetic selection. (2) New neuroimaging techniques could help resolve the controversial question of the treatment of patients in the vegetative state and other impairments of consciousness. I shall clarify the moral significance of consciousness and its relation to the value of life and thereby aid the interpretation of neuroimaging studies and help inform the treatment of such patients. (3) Neuroscience is shedding striking new light on the processes underlying human decision-making, leading neuroscientists and philosophers to cast doubt on the reliability of our moral judgement and thereby on the very practice of biomedical ethics. I will assess this challenge and identify ways in which such research might be used to enhance our moral judgement and improve medical decision-making.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: NEUROLOGICAL
Title: Role of axonal Kv7 channels in regulating hippocampal granule cell and mossy fibre excitability.
Funder: Wellcome Trust

Abstract: Hippocampal dentate gyrus granule cells axons (mossy fibres) and perhaps, their terminals, express a high density of voltage-gated, Kv7.2 and Kv7.3 potassium channels. These underlie the sub-threshold, non-inactivating M-current in neurons. Little, however, is known about the influence of Kv7 channels on granule cell and mossy fibre excitability, or whether modifications in their activity can affect neurotransmitter release from mossy fibre terminals. Using a combination of novel tools such as peptides designed specifically to reduce axonal Kv7 channel activity and pharmacological agents, together with electrophysiological recordings from soma, axon blebs and mossy fibre boutons, we aim to find out how Kv7 channels regulate mossy fibres and bouton intrinsic excitability, action potential (digital) and pre-excitatory synaptic potential (pre-EPSP, analog) signalling in mossy fibres and neurotransmitter release. The work willbe supplemented by immunohistochemical observations on Kv7 subunit localization and distribution. The results will enhance our knowledge of the physiological role of axonal Kv7 channels. Further, given that some Kv7 mutations associated with BFNC have reduced axonal expression in cultured hippocampal neurons and that granule cells are involved in epileptogenesis , the findings may provide us with an insight intohow impaired axonal Kv7 channel function can lead to epilepsy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Neural tube closure: a biological and computational approach to understanding the developmental and folate-protective mechanisms
Funder: Wellcome Trust

Abstract: In early pregnancy, a flat plate of cells on the back of the embryo folds up to form the neural tube , the future brain and spinal cord. Disorders of this process lead to birth defects called neural tube defects (NTDs) in which the brain and/or spinal cord of the fetus become irreversibly damaged. This results in death before birth, or handicap in surviving babies. NTDs affect 1 in every 1,000 pregnancies, with around 130,000 cases per year, worldwide. The risk of NTDs depends on genetic and n on-genetic factors and, importantly, the chance of an affected pregnancy can be reduced if the mother takes folic acid supplements in early pregnancy. Surprisingly, we do not understand how folic acid works in the embryo, making it difficult to improve this therapy in future. In the present research we will use well-established models of NTDs in mice to probe the detailed molecular and cellular processes by which the neural tube forms in the embryo, and the factors that cause the process to go wrong. We will determine how folic acid prevents NTDs in the mice, and we will conduct the first study of the mechanics of neural tube development using a computer simulation technique.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: NEUROLOGICAL
Title: Cerebellar-cortical interactions in health, aging and disease.
Funder: Wellcome Trust

Abstract: The brain has two major parts, the cerebral hemispheres and the cerebellum, that are very heavily interconnected. The roles of many parts of the cerebral hemispheres are becoming clear, but the role of the cerebellum is still uncertain, partly because it operates in tight interaction with the cerebrum and so cannot be studied in isolation. Disease or damage to the cerebellum is relatively common and leads to obvious movement symptoms So theories of the cerebellar function for motor control a re well advanced but still require detailed testing. The cerebellum may play similar roles for complex motor tasks and even cognitive tasks. We propose a programme of experiments designed to elucidate the function of the cerebellum and its interaction with cerebral areas using experiments in healthy subjects, testing performance after magnetic stimulation methods that temporarily block function, and brain imaging analysis to record brain activity and the strength of interactions between area s. We also propose to test patients, to record how cerebral activity changes after cerebellar lesions, and elderly subjects whose cerebellum has declined in volume. This work is critical to allow us to better understand the role of the cerebellum and how its interactions change with learning, with disease and with age.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL