NIHRDataInsights/HRCSData huggingface dataset:
Title: Cell-intrinsic and environmental factors that influence the development and homeostasis of the vertebrate nervous system
Funder: The Francis Crick Institute

Abstract: The main focus of our work is to understand the cellular and molecular mechanisms that govern the development, organisation and maintenance of the nervous system. Our goal is to understand how diverse subtypes of neurons and glia are generated in the embryo and how they establish specific connections to form functional neural circuits. We are also interested in understanding how the assembly and functional organisation of the nervous system is influenced by non-neural tissues (such as the immune system) and environmental factors (such as the microbiota). To achieve these goals we focus our studies on the intrinsic neural circuits of the gut wall, collectively called the enteric nervous system (ENS). The ENS is an exceedingly complex neural network with many types of neurons and glial cells but no obvious topographic organisation. Neurons with different molecular profiles and physiological properties are scattered throughout a network of enteric ganglia and connect in an unpredictable manner. Despite their seemingly chaotic organisation, intestinal neural circuits control highly stereotypic activities of the gastrointestinal tract (such as peristalsis) and mediate stereotypic responses of the gut wall to local and systemic signals. Using in vitro and in vivo experimental models we study how a meaningful functional output of the ENS (such as motility and secretion) emerges from ostensibly disordered neural networks. In particular, we are interested in uncovering genetic programmes and developmental rules that dictate the assembly of functional intestinal neural circuits during embryogenesis. Our studies have provided evidence that environmental factors, such as microbiota, can have dramatic effects on the development and organisation of the ENS in vertebrates. Our focus is on understanding the signalling pathways employed by enteric neural circuits to sense the luminal contents and uncovering downstream molecular cascades that adjust the peristaltic and secretory activity of the gut according to the state and composition of the intestinal lumen. In addition to advancing our understanding of the development and function of the ENS in the context of the normal gut, we also address questions relating to the responses of enteric neurons and glial cells to gut pathology (such as infection and inflammation) and their role in intestinal tissue repair. For our work we employ a wide spectrum of experimental approaches, ranging from cell culture experiments to physiological analysis. Molecular, cellular and imaging approaches are employed in conjunction with genetic manipulations to understand how multiple developmental and environmental signals converge to control gene expression, cellular differentiation and function of the ENS.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;ORAL AND GASTROINTESTINAL
Title: JellyDrops+: Transforming nutrition for elderly people with dementia
Funder: Innovate UK

Abstract: There are 850,000 people with dementia (PWD) in the UK\[1\], with over half experiencing malnutrition and clinically-significant weight-loss\[3\]. Malnutrition has detrimental health consequences including higher risk of associated illness (cancer, COPD, muscle weakness, weak immune system\[9\]), as well as reduced ability to socialise, remain active and independent. Malnourished PWD have 4x higher risk of reaching 'severe dementia' and 3x higher risk of death than non-malnourished PWD\[10\]. The incremental healthcare cost of treating malnourished PWD is also 3x higher\[8\], whereby 70% of hospitalised PWD experience malnutrition\[3\], slowing recovery, and extending hospital stays\[7,8\]. JellyDrops was founded by Lewis Hornby in 2018 due to personal experience of his Grandma (with dementia) needing hospitalisation for dehydration. After living in a carehome for several months, Lewis realised that delivering fluid and nutrients via drinks and traditional delivery methods did not work for many PWD. PWD have a unique set of barriers to drinking liquids (e.g. no longer feeling thirst, inability to use cups, difficulty swallowing liquid), making it difficult/impossible for carers and family to support PWD to consume the fluid and nutrients they need. However, many PWD enjoy sweets. JellyDrops was born. Lewis developed a jelly 'sweet' containing 95% water in a solid form, which was tasty, easy to hold and attractive. The sweets are sugar-free but contain non-laxative sweeteners. One tray of 24 JellyDrops provides 300ml of water and user-testing shows significant wellbeing and health benefits (AppQ3), increasing average daily fluid intake 200-250ml, reducing the frequency of days not meeting fluid targets by 76%. Many PWD choose to eat a tray per day independently, needing little/no encouragement. JellyDrops not only provide essential hydration but also improve social engagement and excitement for PWD and their carers. The existing JellyDrops product has already been tried by 20,000 UK PWD, improving hydration in an engaging way. The multi-award winning (patent-pending) product is rated Excellent on Trustpilot, named the Dementia Innovation of the Year (2020), and supported by the Alzheimer's Society. To tackle the unaddressed issue of malnutrition in PWD and respond to market demand, this project will add nutritional components into JellyDrops, creating JellyDropsPlus(JD+). This project develops a transformational new delivery format for a nutritionally-complete product, overcoming PWD's unique barriers to drinking liquids and difficulty in consuming existing nutritionally-complete drinks. User engagement and people-centred design principles will be critical for this project, utilising established design thinking to ensure JD+ are designed/developed with end-users at the core.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL;ORAL AND GASTROINTESTINAL
Title: The anatomical, physiological, and molecular basis of chronic visceral pain in humans.
Funder: Wellcome Trust

Abstract: Recent estimates indicate that up to 1 in 3 individuals in Western countries experience pain and discomfort from the gastrointestinal tract on a regular basis, sufficient to consult a doctor. Standard diagnostic methods fail to determine a cause for these symptoms in the majority of cases, and therefore there are no effective treatments. It is clear from the applicant s work that many types of gastrointestinal sensory nerves exist in animal models, which change markedly in disease states. Thus h e has identified which types of sensory nerves probably transmit pain, and which biochemical systems underlie their function. Targeting these will hold the key to suppressing pain in humans, but before this can happen, a thorough understanding of human gastrointestinal sensory nerves, including their function, structure, and molecular makeup is required. This will be achieved using novel methods for recording nerve activity from surgical specimens of bowel, and application of drugs and chemicals . It will be complemented by methods to visualize the structure of sensory nerve endings and the receptors they possess that evoke or reduce pain. By understanding how pain is regulated at this peripheral level directly in humans, it is possible to develop more confidently analgesics suited for clinical use.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;ORAL AND GASTROINTESTINAL
Title: Using pelvic floor muscle training to manage incontinence in progressive MS
Funder: Multiple Sclerosis Society

Abstract: What is the project about? Many people with progressive MS will experience continence issues at some point. Experiencing continence issues with the bladder and the bowel can often occur at the same time however they are commonly treated separately. Some early stage research has shown that pelvic floor muscle training (PFMT) can improve both these symptoms in people with MS however these studies have only included women and more research is needed. Dr Cotterill will lead a four-year project to explore the effect of PFMT on bladder and bowel incontinence._x000D_ _x000D_ The researchers will conduct a large scale questionnaire of 800 people with MS who have bladder or bowel incontinence to capture information related to their quality of life, sexual function and general health. 45 of these people will also take part in a treatment study. Of these 45, half of the people will attend group sessions to have PFMT led by a physiotherapist and the other half will have a training booklet about PFMT to work through alone. The researchers will compare which treatment has a bigger impact on continence and quality of life. _x000D_ _x000D_ How will it help people with MS?_x000D_ _x000D_ Experiencing continence issues with bladder or bowel can have a huge impact on quality of life â€“ it can affect confidence and independence. Previous research in this area has been lacking and hasnâ€™t explored the full issue. This project will improve this and could produce a treatment which will make a real difference to peoplesâ€™ lives.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL;RENAL AND UROGENITAL
Title: Midbrain dopamine systems and control of bladder function
Funder: Medical Research Council

Abstract: Even when the bladder is full, adult humans and many socialised species of animal are able to defer micturition until they find themselves in a safe and socially acceptable place. With urge urinary incontinence (UUI) this control is lost. Current drug treatments for UUI target the bladder muscle, with the aim of reducing its excitability. However, the primary cause may lie not in the bladder itself, but in the central control pathways that regulate bladder filling and emptying. At present, the precise location of these pathways and the neurotransmitters employed are not fully understood. Clearly a full understanding of the central control of the bladder is essential before any new treatment for UUI can be developed. Our recent studies on rats suggest that the neuronal ?switch? that controls bladder activity is located in the caudal ventrolateral periaqueductal grey (cvlatPAG) in a region that contains a cluster of dopaminergic neurones. In the proposed study we will investigate the role of these cells in controlling micturition. Using a mouse model we will investigate the effect on bladder function, assessed by bladder cystometry, of selectively lesioning these neurones firstly in urethane-anaesthetised mice and then in conscious mice with indwelling bladder catheters. We will then take advantage of the availability of a mouse strain that has been genetically engineered to express Cre protein in the dopamine-expressing neuronal population. By injecting an adeno-asociated virus expressing rhodopsins to the cvlatPAG and hyperpolarize or depolarize the dopaminergic cell population by laser light initially in acute urethane-anaesthetised mice and then in chronically instrumented animals we will investigate the function of dopaminergic neurons on micturition. In the final part of the study transynaptic viral tracing combined with immunohistochemistry will enable us to investigate synaptic connectivity of the dopaminergic cell group within the micturition control pathway. The new data from the project will provide essential information on central control, which could form the basis for development of new drugs that act to ?normalise? the activity of the bladder control circuits in those individuals with UUI in whom the control has been lost.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;RENAL AND UROGENITAL
Title: Transcutaneous Tibial Nerve Stimulation for the treatment of urinary tract symtpoms in people with Parkinson's
Funder: Dunhill Medical Trust

Abstract: Parkinson's is the second most common chronic neurodegenerative condition in people over 65, with bladder dysfunction affecting up to 71%. Symptoms greatly affect quality of life and include urgency, frequency, hesitancy, nocturia and incontinence. Addressing urinary dysfunction is one of the top 10 priority research areas identified by a priority setting partnership undertaken by the James Lind Alliance and Parkinson's UK due to a lack of evidence for successful treatments. Following a workshp involving people with Parkinson's (PwP) and clinicians the effect of bladder dysfunction and current available treatments were discussed. Transcutaneous Tibial Nerve Stimulation (TTNS) was identified by clinicians and PwP as a possible, simple, non-invasive treatment. Objectives: (1) Implement a standardised training approach and package (already developed) for the correct application of TTNS, (2) conduct an RCT targeting PwP with poorly controlled overactive bladder symptoms to compare the change in bladder symtpoms and quality of life between the two groups, (3) conduct cost-effectiveness analysis to explore if TTNS is cost effective in PwP, and (4) assess fidelity of the intervention. Methods: A randomised controlled trial of 6 weeks with twice weekly TTNS compared to sham TTNS. Particpants will be recruited in 5 NHS neurology/movement disorder services and will be shown by a research nurse how to apply TTNS or sham TTNS themselves at home. Particpants will receive a weekly supportive telephone call from the researchers during the intervention period. The primary outcomes is change in urinary leakage (ICIQ-SF). Secondary outcomes include the IPPS urinary symtpom questionairre, 3-day bladder diary, quality of life, psot-void residual, acceptability and fidelity. We will conduct a health economic evaluation. Outcomes will be measured at 0, 6 and 12 weeks. Preliminary work undertaken by some of the applicants has indicated that a sample size of 208 participants (104 per arm) is required. A statistical analysis plan will be agreed in advance, with analysis of primary and secondary outcomes conducted according to the intention-to-treat principle using linear models adjusted for baseline and minimisation variable. The trial will allow us to determine effectiveness, safety, cost and acceptability of TTNS for bladder dysfunction in PwP. Results will be published in open access journals, lay reports will be posted to all participants and presented at conferences. In addition we will ensure the results are incorporated into treatment pathways and guidelines.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL;RENAL AND UROGENITAL
Title: Control of blood flow and oxygen to the brain of preterm infants undergoing intensive care
Funder: SPARKS

Abstract: Brain blood flow (known as cerebral blood flow, CBF) is normally tightly controlled, but in sick preterm infants this control can be lost resulting in brain injury. Current practice is to monitor and treat low blood pressure, although the relationship between blood pressure and CBF is poorly understood. This study will measure CBF using a non-invasive light monitor. It aims to identify the optimal blood pressure in individual babies, where control of CBF is maximal and will investigate the relationship between lack of control and brain injury and the effects of drugs to increase blood pressure on CBF.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Defining kisspeptin neuronal networks and function in the mouse hypothalamus (Resubmission).
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Kisspeptin neuropeptides are key regulators of GnRH release and activation of the mammalian reproductive axis at puberty. Kiss1 neurons are located in two main regions of the hypothalamus; the AVPV region, which controls the pre-ovulatory LH surge and the ARC region, which controls basal GnRH pulsatility. One of the fundamental steps in understanding how Kiss1 neurons are regulated by upstream signals requires an accurate definition of their neuronal connections. To determine this, we will use a new transgenic mouse line in which Kiss1 neurons express the CRE protein and use conditional viral tracing to define afferent neuronal inputs to Kiss1 neurons. We will use a genetically modified pseudorabies virus (Ba2001) that requires a CRE-mediated recombination event to express the neuronal tracer tau-GFP and the thymidine kinase (TK) gene required for viral replication. The virus will be delivered by stereotaxic injection into either the AVPV or the ARC regions of the hypothalamus to infect sub-populations of Kiss1 neurons. Viral spread visualized by GFP fluorescence will be monitored at different time points after infection to establish the hierarchy of neuronal connections to the Kiss1 neurons. Differences in neural connectivity between males and females will be identified as well as changes that occur during the estrous cycle and in response to sex steroids. We will also test the hypothesis that changes in neuronal connectivity to Kiss1 neurons influence circadian responses, lactational ammenorhea and the decline in fertility with age prior to menopause. The anatomic localization of the labelled neurons will provide insight into their function and their identity will be confirmed by immunohistochemical analysis of their neurotransmitter expression profiles. The functional significance of these neuronal connections will be tested in vivo by central delivery of the relevant neurotransmitters and activation of Kiss1 neurons visualized C-FOS induction.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Fast optical tomography for imaging seizure activity in newborn infants
Funder: Engineering and Physical Sciences Research Council

Abstract: We are proposing to develop a new way of imaging seizures in the brains of newborn babies, by shining light harmlessly across the head. This project is motivated by our recent discovery, using optical techniques, of previously unknown fluctuations in blood volume in the brains of babies diagnosed with seizures. Every year in the UK, over 1000 babies born at term are diagnosed with seizures, and the condition is even more common in infants born prematurely. Seizures usually cause convulsive body movements, and are due to abnormal electrical activity in the brain. This activity can usually be measured using a method known as electroencephalography (EEG). However EEG has significant limitations: it cannot detect activity occurring deep inside the brain and was normal during the unusual blood volume fluctuations we observed optically. Accurate diagnosis is important because seizures are not just a symptom of a medical problem, but are themselves a potential cause of brain injury. The work we propose will lead to better diagnosis and understanding of infant seizures, and underpin research into better treatments. We plan to modify an existing optical imaging system to acquire data simultaneously with EEG measurements, and develop new schemes which enable images to be acquired much faster and with fewer data than is currently possible. This is essential in order to study the fluctuations observed previously, and determine how they evolve over time within different parts of the brain. The research will involve developing a new theoretical analysis, and designing new ways of processing the recorded data to extract the required information. We will also explore a novel way of combining optical and electrical measurements together to provide simultaneous three-dimensional maps of electrical activity and blood volume changes. All the new techniques will be tested on tissue-simulating phantoms before conducting a programme of studies on newborn babies with a high risk of seizures. We also propose to organise a Workshop, inviting other scientists and doctors interested in combining different medical imaging techniques to examine brain activity, in adults as well as children.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Programmable nano-assembly of plasmonic materials for molecular interactions
Funder: Engineering and Physical Sciences Research Council

Abstract: The ability to look at small numbers of molecules in a sea of others has appealed to scientists for years. On the fundamental side we want to watch in real time how molecules undergo chemical reactions directly, how they explore the different ways they can come together, interact and eventually form a bond, and ideally we would like to influence this so that we can select just a single product of interest. We also want to understand how molecules react at surfaces since this forms the basis of catalysis in industrially relevant processes and is thus at the heart of almost every product in our lives. However, most scientific studies take place in precise conditions achieved in the laboratory, such as high vacuum, to select the cleanest possible conditions, but which look nothing like the real world applications they simulate. Hence most knowledge is empirical and pragmatically optimised. We have been working on a completely new way to watch chemistry in an incredibly tiny test tube, itself a molecule. We use a barrel-shaped molecule called a 'CB' that can selectively suck in all sorts of different molecules. Recently, we have found a way to combine these barrel containers with tiny chunks of gold a few hundred atoms across, in such a way that shining light onto this gold-barrel mixture focuses and enhances the light waves into tiny volumes of space exactly where the molecules are located. By looking at the colours of the scattered light, we can work out what molecules are present and what they are doing, with enough sensitivity to resolve tiny numbers. Our aim in this grant is to explore our promising start (that was seeded by EU funding). We aim to develop all sorts of ways to make useful structures that sense neurotransmitters from the brain, protein incompatibilities between mother and foetus, watch hydrogenation of molecules take place, find trace gases that are dangerous, and many others. At the same time we want to understand much more deeply and carefully how we can go further with such ideas, from controlling chemical reactions happening inside the container, to making captured molecules inside flex which can result in colour-changing switches. To make all this happen we take research groups spanning physics and chemistry and completely mix them up, so that they can work together on these very interdisciplinary aspects. We have found this works extremely well. We also involve a number of companies and potential end users (including the NHS) who know the real problems when trying to exploit these technologies in important areas including diagnostics, imaging and catalysis.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: NEUROLOGICAL;REPRODUCTIVE HEALTH AND CHILDBIRTH