NIHRDataInsights/HRCSData huggingface dataset:
Title: Bilateral BBSRC-FAPESP: Behavioural and neuroendocrine mechanisms regulating hydromineral homeostasis - a lifelong perspective
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We are interested in the mechanisms whereby the brain integrates the behavioural and neuroendocrine defence of salt and water balance. Transcriptome analysis has identified genes that are regulated by dehydration in key brain regions that controls salt and water homeostasis. We have found that shRNA-mediated inhibition of one of these genes, Gonadotophin inducible transcription factor 1 (Giot1), in the paraventricular nucleus (PVN) eliminates ad libitum salt appetite. This is reminiscent of the homeostatic deterioration seen in old age, when both thirst and salt appetite are much reduced. In contrast, RNAi mediated inhibition of another dehydration induced gene, small G-protein Rasd1, promoted the ingestion of salt. This is reminiscent of the effect of foetal programming, whereby the adult offspring of dams fed a high salt diet have increased salt appetite. These exciting new results suggest that the PVN is not only important for its neuroendocrine function, namely the elaboration of the antidiuretic hormone vasopressin, but is also a crucial component of the behavioural response to perturbation in salt and water balance. We will now test the hypothesis that these mechanism go wrong in old age and are disrupted by foetal programming. Or aims are now to: i) decipher the molecular mechanisms by which Rasd1 and Giot1 affect the activity of neural circuitries that control behavioural (thirst and sodium appetite) and neuroendocrine mechanisms of hydromineral homeostasis, and to asses how these mechanisms are altered by old age and foetal programming. ii) catalogue dynamic changes in the transcriptomes of sensory, integrative and effector components of the osmo-responsive circuitry as a consequence of both foetal programming and old age, and how these respond to an osmotic challenge. iii) assess the physiological and behavioural roles of novel genes by altering their expression using in vivo somatic gene transfer followed by physiological and behavioural analyses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: Using machine learning to predict painful diabetic neuropathy
Funder: Diabetes UK

Abstract: Diabetic peripheral neuropathy affects up to 50% of patients with diabetes and approximately 50% of these patients develop neuropathic pain. There is still a very limited understanding of the risk factors for painful diabetic neuropathy which arises as a complex interplay of multiple risk factors. Our aim is to apply machine learning in order to identify the most important variables for the emergence of painful diabetic neuropathy and build efficient predictive models for this outcome. To do this we will use data derived from the Pain in Neuropathy Study, a comprehensively phenotyped cohort of patients with painful and painless diabetic neuropathy. Clinical, demographic and psychological variables have been collected and are being followed up prospectively. Additionally, we will use data derived from the large community-based GoDARTS cohort of patients with diabetes mellitus. The ultimate goal is to build a classifier, which predicts the presence and severity of painful diabetic neuropathy. This will give valuable insights into underlying disease mechanisms and the interplay of psychological, clinical and demographic factors and chronic pain. We hope that this will provide a useful tool to identify those patients most at risk of painful diabetic neuropathy to enable early intervention.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: Improving the diagnosis of paediatric mitochondrial disease using high throughput sequencing technologies
Funder: Department of Health (England)

Abstract: Mitochondrial diseases are common genetic disorders caused by defective energy production. They affect numerous organs, making clinical and genetic diagnosis difficult. There are no cures but establishing a genetic diagnosis enables patients and their families access to genetic/reproductive counselling. Our current strategy relies upon functional analysis of a muscle biopsy and selective candidate gene sequencing; unfortunately, half of all children remain genetically undiagnosed. My doctoral project uses new technologies to investigate all known disease genes using blood samples, creating a rapid, cost-effective means of obtaining a genetic diagnosis for most children whilst avoiding an invasive and expensive muscle biopsy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: Wellcome Trust Clinical PhD Programme at Imperial College London: 'Investigation of the physiological role of hypothalamic VIP in the regulation of food intake.'
Funder: Wellcome Trust

Abstract: Vasoactive intestinal polypeptide (VIP) is a neurotransmitter of the secretin/glucagon family, all of whose members inhibit appetite. VIP shares strong homology with pituitary adenylate cyclase activating polypeptide (PACAP). VIP and PACAP bind with equal affinity to the VPAC1R and VPAC2R whilst PAC1R is specific for PACAP. VPAC2R and PAC1R are expressed in the hypothalamus, specifically in nuclei known to regulate appetite. Both VIP and PACAP have been shown to reduce food intake but administration of PACAP, acting via PAC1R, is associated with other behavioural abnormalities. My preliminary experiments have shown VIP powerfully reduces food intake in rodents without any effect on behaviour and that hypothalamic VPAC2R expression is reduced by a 24 hour fast. I will now investigate the physiological role of hypothalamic VIP in the regulation of food intake. To achieve this I will determine the hypothalamic site of action of VIP and the neuronal pathways involved. I will also investigate how chronic increased and decreased hypothalamic VIP expression affects energy homeostasis. This programme of work will characterise the physiological role of VIP in the regulation of food intake and its potential as a target, in the development of novel treatments for obesity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: Characterization of stem cells and the dynamics of neurogenesis in the adult hypothalamus.
Funder: Wellcome Trust

Abstract: A major challenge facing human medicine is the prevention of obesity and treatment of neurodegenerative diseases such as Alzheimers, which respectively arise from the malfunctioning or loss of specific neurons in the adult brain. An envisaged approach is to promote the generation of new neurons from a specialized population of cells called neural stem cells (NSC) that are found in discrete areas of the adult brain. Appetite is controlled by neurons that reside in the adult hypothalamus. For th e first time we have shown that the adult mouse hypothalamus contains NSC and that these cells generate new neurons that associate with its appetite-controlling areas. Thus, it is hoped that eating disorders such as obesity can be prevented or corrected by developing drugs that can modulate the number or functioning of adult hypothalamic neurons. To lay the groundwork for this approach, we will study the NSC of the adult hypothalamus and determine how many and what type of neurons they generate, both in normal mice, and following perturbation of NSC through genetic interventions. These studies will identify key properties and dynamics of NSC and neuron generation in the adult brain that will impact the treatment of obesity and neurodegenerative diseases.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: Molecular Basis of Protein Misfolding Disorders.
Funder: Wellcome Trust

Abstract: Essentially all the complex biochemical processes that take place in living cells depend on the ability of the molecules involved to self-assemble into functional structures. Proteins are the molecules that are essential to enable, regulate and control almost all the chemical reactions necessary to maintain such a balance. In order to function, the majority of our proteins need to fold into specific three-dimensional structures, known as native states. Given the central importance of protein fol ding, it is not surprising that the failure of proteins to fold correctly, or to remain correctly folded, has been found to be the origin of a wide variety of pathological conditions. These conditions include many of the most debilitating, feared and rapidly proliferating disorders in the modern world, such late onset diabetes, and Alzheimer's and Parkinson's diseases. In many of these disorders proteins self-assemble in an aberrant manner into large molecular aggregates, including thread-like s pecies known as amyloid fibrils. Our programme of research is aimed at identifying the molecular basis of protein misfolding disorders. We will address this problem by exploring and defining the underlying molecular basis of protein aggregation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;METABOLIC AND ENDOCRINE
Title: The SEEM study: Safe, Efficient and Enjoyable Mealtimes: Creating a toolkit for families of children who need assistance with eating and drinking - a multi-method investigation.
Funder: Barts Charity

Abstract: Childhood difficulties with eating/drinking and swallowing (neurodevelopmental dysphagia) are an identified priority to reduce preventable deaths and improve children with neurodisabilities? outcomes. Dysphagia signs are under-identified, recommendations are not consistently followed, with limited knowledge about adherence strategy use/effectiveness. This project will support a Speech and Language Therapist to determine current SLT practice through a systematic review and national survey and draw on direct experience from children and family-carers through mealtime videos and an innovative swallow-sound recording tool. A novel video-stimulated dialogue approach will also explore participants? perspectives. Data analysis will determine if and how family-carers respond to dysphagia signs, their adherence to SLT recommendations, non-adherence reasons and best-matched support strategies. The output will be A ?best-practice toolkit? of behaviours to recommend and best-matched adherence strategies to improve mealtime safety and enjoyment.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL;MUSCULOSKELETAL
Title: Preclinical development of novel histone methyltransferase inhibitors for Friedreich's ataxia
Funder: LifeArc

Abstract: Friedreich’s ataxia (FRDA) is a neurodegenerative disease which typically begins during childhood or adolescence and is fatal. In FRDA the molecular mechanisms of disease are associated with making the frataxin gene (FXN) inactive. Molecular mechanisms are the individual actions of chemicals and proteins that play a part in orchestrating cellular processes. The disease is caused by a fault in the FXN gene, which when healthy, provides instructions to cells via a sequence of DNA to produce a protein called frataxin, (whose exact function is unclear). The defective gene causes a part of the DNA instructions – a triplet sequence known as GAA – to repeat over and over again, hundreds of times. This error greatly reduces the amount of frataxin protein produced by the cell. The team at Oxford, led by Dr Richard Wade Martins, screened for chemical probes that restore FXN expression and found a group of compounds which significantly increased frataxin protein. With funding from LifeArc, the team aims to: Generate a series of compounds of suitable stability and potency to test target hypotheses in vitro and in vivo Test the efficacy and safety of the compounds in types of stem cells derived from FRDA patients and differentiate these into the specific cell types most affected by reduced frataxin Study the in vivo expression of FXN after treatment in a novel FRDA mouse disease model developed by the team.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;MUSCULOSKELETAL
Title: Neurogenic bowel dysfunction associated with spinal cord injury, multiple sclerosis and spina bifida.
Funder: Department of Health (England)

Abstract: Neurogenic bowel dysfunction in spinal cord injury, and other central neurological conditions, results in faecal incontinence or severe constipation, or more often both, with devastating impact on quality of life. Measuring outcomes is important in evaluating this area of healthcare, and for rigorous research into new and established treatment modalities. The aim of this research study is to develop and validate an outcome measure which accurately reflects what individuals want from interventions used to manage this problem, and which would be suitable for use in clinical and research settings. This award will allow me to broaden my clinical expertise to conditions other than spinal cord injury, and to develop skills in qualitative research methods and systematic literature reviewing. I plan to extend my clinical work to include individuals with other central neurological conditions, and will continue to conduct research exploring and evaluating new and established methods of bowel management.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: NEUROLOGICAL;ORAL AND GASTROINTESTINAL
Title: Exploring novel neurostimulation based therapies for swallowing impairments in Parkinson's
Funder: Parkinson's UK

Abstract: At least a third of Parkinson's Disease (PD) patients experience dysphagia, which can result in malnutrition, dehydration and worsen quality-of-life. In the UK, PD patients consider current management for dysphagia inadequate. Recenty, several neurostimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), have been examined with the prospect to provide neurorehabilitation for limb functions, yet there are no such studies for dysphagia in PD. Previously, we studied the influence of dopaminergic medication (Levodopa) in PD patients with and without dysphagia. We noticed differential cortico-bulbar outputs to transcranial magnetic stimulation of patients with dysphagia compared to non-dysphagic PD of similar age and PD severity. Our results imply that restoration of these observed brain perturbations may favourably influence dysphagia. Here, we propose a placebo-controlled feasibility, cross-over study with 66 patients with idiopathic PD, recruited over 28 months, to investigate the effects of 3 different neurorehabilitation methods, that have been developed and trialled at our department and have shown the potential to produce changes at a brain level in health and disease. These neurorehabilitation paradigms are: inhibitory (1Hz), excitatory rTMS (5Hz) and Pharyngeal Electrical Stimulation (PES). All patients will be randomised to one of the 3 treatments and will receive a real and sham intervention. Our project will help to identify which is the most beneficial and/or best tolerated neurorehabilitative approach for dysphagic PD patients, the level and the extent of changes that can be promoted in PD and will serve as a prelude for multi-center trials in the future.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL;ORAL AND GASTROINTESTINAL
Title: ERA-NET NEURON: The Gut Microbiome in Neuroinflammation and Neurodevelopmental Disorders
Funder: Medical Research Council

Abstract: Neurodevelopmental disorders (NDD) appear during nervous system development and maturation and originate from a variety of genetic and environmental causes or a combination of both. NDDs result in lifelong intellectual disability and behavioural alterations (anxiety, hyperactivity, social impairment, communication deficits) and have therefore extremely heavy socio-economical consequences. Neuroinflammation is one of the hallmarks shared by NDD, including Down syndrome (DS, 1:800), Fragile X syndrome (FXS, 1:6000) and Autism Spectrum Disorders (ASD, 1:100). Recent studies demonstrate the existence of a gut-brain axis through which the intestinal microbiota is able to modulate inflammation. The μNeuroINF project is driven by our hypothesis that the gut microbiome modulates neuroinflammation impacting metabolism and behaviour and contributing to NDD pathophysiology. By studying common effects across three mouse models of NDD: i) the Fmr1-KO mouse model of FXS, ii) the Ts65Dn trisomic mouse model of DS, and iii) the Maternal Immune Activation (MIA) ASD mouse model, we aim to unravel mechanisms by which gut microbial metabolites modulate neuroinflammation and contribute to NDD-related behavioural phenotypes. Our three specific objectives are: 1) to acquire complete metabolomic, metagenomic and metaproteomic neuroinflammatory signatures in three NDD mouse models, 2) to identify microbial metabolites modulating neuroinflammation in NDD, 3) to screen their pharmacological targets and test in vivo their effect on neuroinflammation and behaviour. Meta-"omics" will reveal microbial genes, proteins and metabolites associated with variations in brain cytokines, immune cell populations and behavioural phenotypes in NDD. Microbial metabolites will be screened for pharmacological targets such as receptors and kinases, and mechanisms will be validated in vivo to explore the modulatory role of the gut microbiome on immunity and behaviour. This will ultimately lead to novel personalised medicine and therapeutic strategies for NDD and neuroinflammation, driven by the gut microbiome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;ORAL AND GASTROINTESTINAL
Title: ERA-NET NEURON: Investigation of the neuroinflammatory basis of the human type I
Funder: Medical Research Council

Abstract: Studies of Aicardi-Goutières syndrome (AGS) have proven of major scientific importance by directly informing the biology of infection - particularly HIV-1 (e.g. Nat Immunol 2010; 11: 1005-13; Nature 2011; 474: 654-7), interferon metabolism (e.g. Cell 2008; 134: 587-98), DNA maintenance (e.g. Cell 2012; 149: 1008-22; Nature 10.1038/nature13292), and retroelements (e.g. Nat Immunol 2014; 15:415-422). AGS is undoubtedly a neuroinflammatory disease, as evidenced by its remarkable clinical mimicry of in utero viral infection (e.g. Dev Med Child Neurol 2008; 50: 410-6), a robust association with elevated cerebrospinal fluid white cell counts, intrathecal overproduction of the primary antiviral cytokine interferon (e.g. J Neurol Sci 1988;84:201-8) and the inflammatory marker neopterin (Dev Med Child Neurol 2009; 51: 317-23), the recent observation of brain-reactive autoantibodies (Ann Rheum Dis annrheumdis-2014-205396), and the notable observation of a progressive inflammatory encephalopathy in a transgenic mouse model chronically producing interferon alpha from astrocytes - which recapitulates the neuroimaging and pathological features of AGS, and some viral encephalopathies, to a remarkable degree (J Immunol 1998; 161: 5016-26; Brain Res 1999; 835: 46-61). Although much is now understood about the genetic basis of AGS, very little is known of the mechanics of innate and adaptive immune system engagement directly relevant to the, primary, neurological phenotype - not least because, considering the sensitivities around infant post-mortem examination, particularly where a diagnosis has already been reached, neurological tissue from patients affected by AGS is extremely scarce. Here we propose a multidisciplinary study of AGSassociated neuroinflammation. Our project, combining expertise of high order (spanning mouse and human biology), involves a portfolio of complementary but discrete approaches - thus mitigating risks related to any one particular aspect of the project. In pursuing these studies, including the use of stateof-the-art iPSC and deep sequencing technologies, we will derive data informing the future treatment of the devastating AGS phenotype (across all the recognised genotypes), and which may also be relevant to our understanding of congenital infection, the biology of HIV-1, and neuro-lupus.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;ORAL AND GASTROINTESTINAL
Title: A multi-centre evaluation of the post-gastrostomy management in patients with Amyotrophic Lateral Sclerosis (PostGas)
Funder: MND Association

Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating terminal illness, causing a progressive weakness of muscles controlling movement, swallowing and breathing. Malnutrition and weight loss in patients with ALS are associated with increased disability and shortened survival, especially for those experiencing swallowing difficulties. Long-term nutritional support for patients with severe swallowing problems can be achieved by placing a feeding tube, known as a gastrostomy, directly into the stomach. Our recent research suggested the optimal method of, and timing for, gastrostomy insertion in patients with ALS; however, there is lack of evidence to indicate the optimal ways for the nutritional management of patients with ALS, following gastrostomy insertion. This may explain the worrying finding we identified; that the majority of patients continue to lose weight or make insignificant gains in weight following gastrostomy. The main aim of this study is to evaluate the current clinical practice in relation to the post-gastrostomy nutritional care of patients with ALS; understand further the nutritional requirements of patients, particularly the quantity and quality of nutritional support that patients receive after gastrostomy; and to explore the factors than can lead to continuing weight loss after the procedure. We plan to observe a group of patients who have undergone gastrostomy. We will prospectively collect information about the different post-gastrostomy nutritional approaches and their effectiveness on the nutritional state of patients with ALS (e.g., what feeding regimens patients receive, how caloric intake requirements of patients are calculated). The output of PostGas will help develop evidence-based guidelines for the post-gastrostomy management of patients with ALS.


Research activity codes: 6.4 SURGERY;7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL;ORAL AND GASTROINTESTINAL