NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding the role of pathological cleavage in TDP-43 phase-separation
Funder: Alzheimer's Research UK

Abstract: Most forms of dementia are associated with the formation of aggregates containing specific proteins. Despite tremendous progress in the past decades, researchers still lack a thorough understanding of how and why these aggregates form in the complex context of the human body where proteins may be cleaved in ways that can drastically change the protein properties and tendency to aggregate. With this limited view, therapeutic development is stagnating. We propose to investigate the aggregation of the protein TAR DNA binding protein 43 kDa (TDP-43), which is associated with several forms of dementia, including frontotemporal dementia, Alzheimer’s and Parkinson’s disease, and responsible for the relentless amyotrophic lateral sclerosis. TDP-43 aggregates isolated from patients contain several differently-long fragments of the protein. To unveil how cleavage affects the aggregation of TDP-43, we will use a combined research strategy based both on highly controlled and more complex biological setups. Our strength relies on the ability to develop antibodies - the biomolecules involved in the immunological response of the body - that can help in diagnosis and mechanistic studies. These molecules will allow us to isolate and study how cleavage changes the behavior of TDP-43.

Lay abstract: Most forms of dementia are associated with the formation of aggregates containing specific proteins. Despite tremendous progress in the past decades, researchers still lack a thorough understanding of how and why these aggregates form in the complex context of the human body where proteins may be cleaved in ways that can drastically change the protein properties and tendency to aggregate. With this limited view, therapeutic development is stagnating. We propose to investigate the aggregation of the protein TAR DNA binding protein 43 kDa (TDP-43), which is associated with several forms of dementia, including frontotemporal dementia, Alzheimer’s and Parkinson’s disease, and responsible for the relentless amyotrophic lateral sclerosis. TDP-43 aggregates isolated from patients contain several differently-long fragments of the protein. To unveil how cleavage affects the aggregation of TDP-43, we will use a combined research strategy based both on highly controlled and more complex biological setups. Our strength relies on the ability to develop antibodies - the biomolecules involved in the immunological response of the body - that can help in diagnosis and mechanistic studies. These molecules will allow us to isolate and study how cleavage changes the behavior of TDP-43.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Whether stimulation of the serotonergic 5HT1A receptor can become a safe and clinically convenient way to increase oxytocin function in the brain.
Funder: Wellcome Trust

Abstract: Oxytocin is a peptide known for its ability to enhance social behaviour in both animals and humans. Its effects following intranasal administration have been found to be beneficial in situations where a schizophrenic, autistic or socially anxious person is unable to correctly perceive the social cues that indicate appropriate social engagement. Whilst intranasal sprays are an acceptable form of oxytocin administration with rapid brain uptake, it can be difficult to ensure accurate delivery of th e intended dose and inconvenient for the young or distressed individual. The aim of this study is to examine the possibility of pharmacologically inducing the sustained secretion of oxytocin by an indirect mechanism using the more common approach of oral administration and one which is amenable to long term exposure. I propose that this could be achieved indirectly by pharmacological stimulation of the brain 5-hydroxytryptamine 1A receptor. 5-HT1A agonists have been available for some time but t hose commercially available such as buspirone are not sufficiently powerful at the receptor to enhance oxytocin release. Our aim is to evaluate two new compounds currently in development for the treatment of depression (vortioxetine) and female sexual dysfunction, flibanserin which both have high affinity and efficacy at 5-HT1A receptors.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Navigation to improve outcome of epilepsy surgery
Funder: Wellcome Trust

Abstract: Navigation to improve outcome of epilepsy surgery', Principal Investigator- Professor John Duncan (UCL). The successful neurosurgical treatment of epilepsy depends on complete removal of the part of the brain that gives rise to epileptic seizures, and in avoiding damage to brain areas and pathways critical for functions such as vision, language, sensation and motor control. Achieving these goals requires accurate 30 planning of the surgical approach and resection and real time feedback during the course of surgery. This project builds upon our EpiNA V platform to visualize brain structures that need to be removed to cure epilepsy, and those that need to be spared, in order to avoid adverse effects. This anatomical guidance will be displayed to the surgeon via a neurosurgical navigation interface so that brain tissue removal is optimised, in terms of maximising the chances of remission of the epilepsy and avoiding complications such a loss of part of the field of vision and of language abilities.

Lay abstract: The successful neurosurgical treatment of epilepsy depends on complete removal of the part of the brain that gives rise to epileptic seizures, and with avoiding damage to brain areas and pathways that subserve critical functions such as vision, language, sensation and motor control. Achieving these goals requires accurate 3D planning of the surgical approach and resection and real time feedback during the course of surgery. We will build on our current platform to visualize brain structures that need to be removed to cure epilepsy, and those that need to be spared, to avoid adverse effects. This anatomical guidance will be presented to the surgeon via the neurosurgical navigation system so that the resection is optimal in terms of maximising the chances of remission of the epilepsy and avoiding complications such a loss of part of the field of vision and of language abilities.

Research activity codes: 6.4 SURGERY
Health categories: NEUROLOGICAL
Title: Developmental Mechanisms of Motor Network Tuning
Funder: Wellcome Trust

Abstract: Activity is required for correct development of neural circuits and emergence of appropriate behaviour. At early stages activity is spontaneously generated, and then superseded by patterned network activity as sensory afferents become active. A period of maximal plasticity, termed critical period, generally spans these two phases. Significantly, aberrant activity during neural circuit development, especially when occurring in the critical period, can lead to network errors that become ‘locked in’ and may contribute to neurological disorders in later life. Whilst a requirement for activity is universal for circuit development, important questions remain unanswered. We have identified a comparable requirement for activity in the development of the motor circuit of Drosophila larvae. Notably, perturbation of activity leads to permanent and significant errors in circuit function. This system is composed of identifiable, tractable neurons of defined connectivity. These advantages allow us to study fundamental questions in ways not possible in higher organisms. Exploiting this exceptional level of resolution, our overall goal is: to generate detailed understanding of the cellular and molecular processes that underlie normal network tuning and lead to errors following early activity perturbation; further, to determine in this tractable circuit the capability of homeostatic mechanisms to compensate for early induced perturbations.

Lay abstract: Developing neural circuits are reliant on activity for appropriate development. Moreover, abnormal activity levels are now believed to produce errors in development that can be ‘locked-in’ contributing to diseases such as epilepsy, autism and schizophrenia. Whilst activity is required through much of neural circuit development, periods of heightened plasticity, termed critical periods, during which activity has maximal effect have been identified. How activity tunes a developing neural circuit and the specific events that occur during a critical period, is poorly understood. The potential for neural circuits to rectify errors induced by altered activity during development is also unknown. We address these issues, using larvae of the fruitfly Drosophila. Its nervous system forms within a few hours, has a defined developmental timeline and exhibits critical periods. The tractability of this insect nervous system will allow us to identify how activity refines the development of a neural circuit to ensure appropriate function.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Multi-modal high resolution preclinical PET+SPECT+CT scanner
Funder: Wellcome Trust

Abstract: The University of Liverpool (UoL) and its vicinity lacks in vivo nuclear and CT imaging capability for small animals. To address this critical need, we are requesting an integrated PET+SPECT+CT scanner. The proposed scanner is the only preclinical PET+SPECT+CT on the market that allows simultaneous detection of SPECT and PET probes at sub-millimetre resolution, with the additional advantage that its small foot-print will enable it to be housed within UoL’s purpose-built Centre for Preclinical Imaging. Many potential collaborative research projects cannot currently be facilitated at UoL due to the lack of this imaging capability, despite their potential for scientific excellence and for generating novel, highly impactful results. The equipment will enable users to gain unprecedented insights into the mechanisms underlying various diseases as well as evaluating the safety and efficacy of novel therapeutic interventions. If funded, the PET+SPECT+CT scanner would significantly enhance a variety of already-funded research programmes at UoL in the fields of regenerative medicine, tropical disease (snake envenoming), arthritis, cancer and pharmacology. Furthermore, by advancing UoL’s whole-animal imaging capability beyond the current state-of-the-art, the scanner will enable new projects to be developed, will spur collaboration with nearby Universities, and facilitate industry-academia collaboration in the field of preclinical imaging.

Lay abstract: Imaging has provided some of the most significant breakthroughs in medicine, leading to new ways of diagnosing disease and monitoring the effects of novel treatments. Two important techniques known as ‘PET’ (Positron Emission Tomography) and ‘SPECT’ (Single Photon Emission Computed Tomography), which work by detecting radioactive tracers in the body, have been key to many of these breakthroughs. However, before being used in patients, novel applications involving PET and SPECT need to be tested first in animals to make sure they are safe and effective. The University of Liverpool has exemplary track record in developing new and improved treatments for various conditions ranging from tropical diseases to HIV, liver disorders and cancer, but further progress is limited because we currently lack PET and SPECT for small animals. The proposed three-in-one PET+SPECT+CT scanner will enable more rapid and effective evaluation of our novel diagnostic probes and therapies, thereby expediting clinical translation.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Imaging Focal Epilepsy in Children: A Developmental Perspective
Funder: Wellcome Trust

Abstract: Focal cortical dysplasias are common causes of treatment-resistant epilepsy in childhood, but are persistently difficult to detect on clinical magnetic resonance imaging (MRI) scans by routine visual inspection. This is especially true in children, where pathology may be masked by the dynamically changing background of the developing brain. My fellowship will investigate focal epilepsy in the context of the developing human brain. I will build analytical tools from clinical MRI data to better detect subtle MRI lesions and, using quantitative MRI (qMRI), translate these tools so they can be applied across clinical sites and in other neurodevelopmental and neurological disorders. I propose to build a continuous time-space model of brain development using large population MRI data from typically developing children. Using this model, I will test the specificity of abnormality maps in individual patients to confirmed epileptic pathology in a training- and test-dataset from two large epilepsy neurosurgery programmes. To generalise this model to standard clinical sequences, I will collect qMRI and synthesise scanner-independent MR images to tailor this growth model to any local protocol. Finally, I will extend these structural findings to identify networks associated with focal epilepsies, and investigate whether they can predict a successful outcome from surgery.

Lay abstract: Epilepsy is the most common neurological disorder in children. Around 30% of children with epilepsy do not respond to medical treatment and, for these patients, surgical removal of the seizure generating brain tissue may be an effective treatment. Identifying regions in the brain that cause seizures using magnetic resonance imaging (MRI) is a good predictor as to whether an individual will have a good outcome after surgery. In infants and children however, identifying these on MRI is complicated by the extensive changes occurring during normal brain development and variability in how brain images are collected at different hospitals. To address this problem, I plan to investigate how the brain develops in a group of children without epilepsy and will try to predict, in children with epilepsy, where there is a brain abnormality. For this fellowship, I have drawn together an international consortium of collaborators with widespread expertise and a critical mass of data. I will address these questions by creating models of early brain development in both health and disease. By the end of the fellowship I plan to develop and release analytical tools that will help inform future clinical decision making in epilepsy and related neurological and neurodevelopmental disorders.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Dissecting endolysosomal trafficking defects in Parkinson's disease
Funder: Wellcome Trust

Abstract: Endolysosomal trafficking defects are increasingly being implicated in Parkinson's disease (PD). In particular, a number of genes associated with lysosomal storage disorders (LSDs) have been identified as risk factors for developing PD. The precise mechanisms linking endolysosomal genes to PD are not fully understood, but are likely to involve common pathogenic mechanisms. Therefore, through developing a greater understanding of these pathogenic processes, we aim to discover new therapeutic targets in PD. To do this we will study a number of PD-linked genes, including LSD-genes (GBA1, SMPD1, NAGLU, SLC17A5 and ARSB) and Rab39B, encoding an endosomal Rab GTPase. Specifically, we will create novel knockout models of these genes using Drosophila and human PD neuronal cultures, in addition to performing advanced genetic studies. The latter will include a genome-wide association study on the Drosophila Genetic Reference Panel of >200 inbred fly lines harbouring LSD gene loss-of-function. The common biological pathways and genes associated with protection against PD will be identified and compared to those detected by transcriptomic analysis using RNA-sequencing. Targeted genetic and therapeutic drug screening will also be performed on the PD flies. Novel therapies and therapeutic targets will be validated in iPSC-derived dopaminergic neurones and brain tissue from PD patients.

Lay abstract: Nerve cells move proteins around the cell and break them down using a special transport and waste disposal system called the endolysosomal pathway. The correct functioning of this system is looked after by many genes. Some of these genes are damaged in Parkinson’s disease, a common illness causing abnormal movements. We will study these genes using a popular laboratory organism, the fruit fly. We will study what happens when we block these genes from working in the fly brain. We will also look at genes in many flies with damaged endolysosomal systems, to see which genes make the flies less likely to become sick. In doing so, we hope to discover new drugs and sites that drugs can work on to prevent Parkinson’s disease. These will then be tested in nerve cells developed from human stem cells, and successful drugs will be tested in Parkinson's disease patients in the future.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Highly sensitive brain blood flow measurements using ultra-high field magnetic resonance imaging
Funder: Wellcome Trust

Abstract: Blood flow is critical for maintaining the steady supply of oxygen and nutrients to the brain, and blood flow changes are present in a range of diseases including stroke and dementia. Conventional methods for in vivo blood flow mapping have limitations and often cannot be used for longitudinal monitoring or research. In this proposal I aim to develop highly sensitive imaging methods for measuring brain blood flow based on a non-invasive magnetic resonance imaging technique, arterial spin labelling, applied at ultra-high field. The main goals of this research are: 1. To establish a robust platform for ultra-high field arterial spin labelling by developing novel approaches to overcome a range of technical challenges associated with this technique; 2. To develop advanced imaging approaches which allow richer cerebrovascular information to be obtained, including high resolution angiography and vessel-selective imaging; 3. To demonstrate the high sensitivity achievable with these novel methods by measuring changes in white matter perfusion in patients with vascular cognitive impairment, and probing the brain’s response to tonic pain at unprecedented spatial resolution. These new methods will be actively shared with local, national and international collaborators, enabling previously unfeasible clinical and basic science research studies to be performed.

Lay abstract: The brain is dependent on a continuous supply of blood to function effectively. Disruption to blood flow, or “perfusion”, in the brain is linked to a range of diseases, including stroke and dementia. In this proposal I aim to develop highly sensitive new methods for mapping brain blood flow based on a non-invasive magnetic resonance imaging technique, arterial spin labelling. I will use a scanner with a very strong magnetic field, enabling much sharper images to be produced in shorter scan times than is normally possible. I will then use the improved sensitivity of these new techniques to gain new insight in two important areas: investigating perfusion changes in patients with dementia and gaining a deeper understanding of how the brain responds to pain. Ultimately, these methods will lead to a better understanding of disease and improved care for patients with a wide range of conditions.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Study of Neuronal Antibodies in Peadiatric Epilepsy
Funder: Wellcome Trust

Abstract: In patients with new-onset refractory status epilepticus, 48% of have an autoimmune aetiology. Moreover, neuronal autoantibodies (e.g. N-methyl-D-aspartate receptor antibodies (NMDAR-Abs)) are found in 10-30% of children and adults with less severe epilepsy, most commonly in focal drug-resistant cases. These data underline the scale and the seriousness of autoimmune epilepsy (AE). Immunotherapy is the mainstay of treatment, but is often slow to work (a key issue in refractory status, where time is critical) and risks significant side-effects. In my NMDAR-Ab AE model, receptor-specific treatment with the neurosteroid pregnenolone sulphate (PS) counteracts the autoantibody effect at the neuronal membrane level leading to rapid and specific reversal of NMDAR-Ab mediated electrophysiological changes. Pregnenolone, the precursor to PS, has been successfully used in clinical trials as an adjunctive treatment in schizophrenia patients [33-35], demonstrating its safety, and highlighting the potential for future drug trials. My proposed research will investigate other neuronal antibodies, e.g.to the gamma-aminobutyric acid A receptor, elucidate their pathogenicity and epileptogenicity using AE models, and treat them with receptor-specific, existing, licensed treatment. This approach directly addresses the unmet clinical need for rapid intervention in autoimmune epilepsy, reduced side-effects from immunotherapy and prevention of persistent cognitive problems, thereby improving long-term paediatric outcomes.

Lay abstract: An autoimmune disease is one in which the immune system, a defending army intended to protect our body from external agents, attacks the body's own healthy cells and tissues which are mistakenly perceived as foreign or abnormal. This causes production of substances called auto-antibodies that target our own cells. When the targets of this attack are healthy brain cells (neurons) and their important proteins, patients suffer from seizures and epilepsy. The main existing treatments dampen the body's abnormal immune response (immunotherapy, e.g. steroids). This has significant side effects as healthy cells are also affected. My research will find out why these brain autoantibodies cause epilepsy and seizures, and develop treatments that work to reverse the damage caused by the disruption of the particular brain protein under attack as well as targeting the immune system. This would mean a quicker recovery, lower doses of immunotherapy and improved long-term brain function.

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