NIHRDataInsights/HRCSData huggingface dataset:
Title: Peripheral gate in somatosensory system
Funder: Wellcome Trust

Abstract: Peripheral nerves are responsible for haptic, somatic and visceral sensations including that of pain. Healthy nerves conduct action potentials from their peripheral endings to the dorsal spinal cord, where synaptic transmission first takes place. It is assumed that the peripheral somatosensory signals are first integrated in the spinal cord and subsequently analysed in the brain. Our recent findings has challenged this view and suggested that peripheral somatosensory ganglia (such as dorsal root ganglia, DRG) are capable to regulate pain transmission utilising GABAergic somatic cross-talk mechanisms. I hypothesize that somatosensory ganglia represent a new type of a ‘gate’ within the somatosensory system. My overarching goal is to develop a comprehensive mechanistic understanding of the peripheral somatosensory gating. I will use in vivo electrophysiology, mouse transgenics, chemo- and optogenetics, behavioural models and other cutting-edge approaches to address the following specific aims. (1) Secure direct in vivo evidence for peripheral somatosensory integration at the DRG. (2) Moving beyond GABA: identify other major ganglionic communication mechanisms. (3) Elucidate physiological context of signal integration in the DRG. (4) Identify subcellular structures involved in somatic integration. These studies will change current understanding of somatosensory processing and will provide new ideas for pain treatment at the periphery.

Lay abstract: Peripheral nerves respond to changes at the surface or inside our body, the brain then interprets these responses in terms of tactile or visceral sensations, such as heat, touch, or pain. Until now, accepted scientific theory has held that only the central nervous system could interpret and analyse such sensations. The peripheral nerves were seen to be a mainly wiring network, relaying information to and from the central nervous system by delivering messages to the ‘control centre’ (the brain), which then tells the body how to react. Our recent findings challenge this view and suggest that peripheral nervous system could be capable of interpreting its environment and modulating pain. My overarching goal is to develop a comprehensive mechanistic understanding of how peripheral nerves can regulate and control pain. These studies will change current view on the principles of somatosensory processing and will provide new ideas for pain treatment.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neuroinflammation and its role in precision physiotherapy for patients with entrapment neuropathies
Funder: Wellcome Trust

Abstract: Entrapment neuropathies are the most common conditions causing nerve-related pain. Even though Physiotherapy is the recommended treatment, research suggests only modest benefits. A major road-block is the lack of adequate patient stratification. My fellowship will address this by investigating the role of neuroinflammation in precision physiotherapy. The key goals are to 1) characterise human neuroinflammation, 2) validate magnetic resonance neurography (MRN) as a non-invasive marker and 3) determine whether physiotherapeutic exercises (neurodynamics) can reduce neuroinflammation. I will use longitudinal cohorts of patients with carpal tunnel syndrome (CTS) and Morton’s neuroma undergoing surgery as model systems with unparalleled access to injured tissues (e.g., nerve, skin, tenosynovium, blood). I will characterise neuroinflammation and its relationship to symptoms in these samples using gene/protein expression and histological analyses. By directly comparing MRN with histological findings, I will determine its validity as a non-invasive marker for neuroinflammation. I will then perform a mechanistic trial to investigate whether neurodynamic exercises reduce neuroinflammation by measuring MRN before and after exercises or control interventions in CTS patients. My project will provide novel biological insights into neuroinflammation, and may revolutionise its clinical detection. The development of precision physiotherapy has high potential to reduce patients’ suffering and decrease healthcare costs.

Lay abstract: Compression neuropathies are the most common cause for nerve-related pain. Even though Physiotherapy is the recommended treatment, research suggests only modest benefits. I will explore whether the detection of nerve-inflammation could be used to develop precision physiotherapy (direct the right treatments to the right patients). I will first characterise the molecular and cellular components of nerve-inflammation and their relationship to symptoms in tissues of patients with carpal tunnel syndrome (CTS) and Morton’s neuroma (nerve, skin, tendon-sheath and blood). I will also determine whether advanced neuroimaging (MR neurography) can be used to detect nerve-inflammation. I will then investigate whether physiotherapy exercises can reduce nerve-inflammation in patients with CTS by performing MR neurography before and after physiotherapy or control interventions. My project will discover more about the biology of nerve-inflammation, and may revolutionise its clinical detection. Importantly, my findings will facilitate the development of precision physiotherapy, thus decreasing suffering and healthcare costs.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Physiological and behavioral functions of the basal ganglia
Funder: Wellcome Trust

Abstract: The basal ganglia are implicated in a wide range of behaviors and are particularly important for many types of learning. The diversity of basal ganglia function is tied to cortical diversity; indeed, the entire cortex outputs to the basal ganglia, which is routed in a loop via the thalamus back to the cortex. These three components of the cortex, basal ganglia, and thalamus likely form an archetypal circuit which carries out similar computations in the perceptual, cognitive, and motor domains. The way in which activity propagates across these structures, and how this propagation changes to support learning, are largely unknown. I propose to investigate the interdependence within this circuit by building on my prior work on communication between the cortex and striatum. In those experiments, I developed methodology towards defining the functional relationship between structures, and identified specific learning-induced changes. Here, I will trace those changes across structures throughout learning, I will determine how these changes affect the little-studied output arm of the basal ganglia, and I will causally determine which connections within this circuit drive specific components of both activity and learned behavior. These experiments will contribute toward a holistic understanding of a major neural circuit.

Lay abstract: Brain structures work in concert with each other, which can create a chicken-and-egg situation when trying to understand how the brain supports learning: where do learning-related changes first arise? And which connections and changes drive the new behavior? This problem is particularly relevant in a neural circuit consisting of a loop from the cortex, to the basal ganglia, to the thalamus, and back to cortex. This circuit is responsible for learning and executing myriad behaviors, but likely performs similar operations for these behaviors, such that understanding one well-defined aspect will inform a general understanding of how these structures work together. I will tackle this by studying changes in visual activity across these structures while mice learn to move an object on a screen. These experiments will contribute towards understanding how these structures work together, which in the future can be applied towards what goes wrong in disease states.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Recovering respiratory motor and muscle function after severe spinal cord injury
Funder: Wellcome Trust

Abstract: Using an innovative cross-disciplinary approach, I will directly explore the pathophysiology, function, and mechanisms of respiratory motor recovery following severe spinal cord injury (SCI) and determine if restoration of this activity is sufficient to mitigate increased rates of morbidity and mortality caused by acquired infections.Treatment strategies for SCI have focused on restoring spinal neuronal circuitry. I will determine if a novel treatment strategy which targets both neural growth/plasticity in the spinal cord and muscle mitochondrial activity, can restore systemic respiratory motor function after severe SCI. I will use innovative techniques including bi-planer X-ray videography and ventilatory pattern variance to assess the pathophysiology of the respiratory system following injury and recovery. Further, in physiologically relevant conditions, I will assess cyclical power generated by respiratory muscles, alterations in neuronal circuitry, and model changes in muscle oxygen transport to determine the systemic mechanisms behind respiratory deficit and recovery. Finally, most SCI patients show increased morbidity and mortality with reduced functional activity due to post-injury acquired pneumonia infections. For the first time, I shall assess whether my combined treatment strategy can overcome the deleterious effect of pneumonia infection and the mechanisms through which sustained systemic functional respiratory recovery can occur.

Lay abstract: Respiratory failure is the leading cause of morbidity and mortality following spinal cord injury (SCI) due to the trauma and common post-injury acquired pneumonia infections. However, there exists no effective SCI clinical treatment. SCI causes damage throughout the respiratory system (including the spinal cord, muscles and connective pathways) which spinal therapies alone do not recover. I will determine whether a novel treatment strategy targeting both spinal and muscle recovery can cause profound respiratory restoration after SCI. I will use advanced experimental models and imaging to determine the physiological changes and mechanisms of injury and recovery and employ computer modelling to assess these changes. Finally, I will determine if, and how, my combination treatment strategy has enabled sufficient respiratory recovery to overcome the functional deficits caused by infection. This research is critical to the development of SCI treatment strategies for respiratory dysfunction and advancing our understanding of neurological injury and recovery.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Dynamic Heterogeneity and Neurogenic Potential of Enteric Glia
Funder: Wellcome Trust

Abstract: Tissue maintenance and repair depend on stem cells that replenish cellular compartments reduced by physiological turnover or disease. Despite the essential function and unavoidable attrition of the enteric nervous system, a major branch of the peripheral nervous system that controls digestive physiology and gut homeostasis, the mechanisms controlling its cellular integrity and regeneration remain unknown. We will test the hypothesis that mammalian enteric glial cells (EGCs) exhibit neural stem cell activity and determine whether this is a property of a defined EGC sublineage or can be exhibited by a wider population of EGCs. As a first step, we will define the transcriptional hetrogeneity of EGCs and uncover the dynamic behaviour of moleculary defined supopulations during homeostasis or in response to gut pathology. Quantitive analysis and intavital imaging will inform the dynamics of EGCs within the gut microenvironment. The generation and functinal integration of enteric neurons into intestinal neural circuits will also be analysed.Finally, we will characterise niche signals and cell intrinsic transcriptional programmes that control fate decisions of EGCs, namely their choice to remain quiescent, enter the cell cycle and differentiate into neurons. Our work will advance the fields of neural stem cells, glia cell biology and gastroenterology.

Lay abstract: The gastrointestinal system is essential for digestive function and health. Not surprisingly, the complex physiological processes of digestive function are controlled by intricate regulatory systems, including vast neural networks that are embedded within the wall of the entire gastrointestinal tract. As in other parts of the nervous system, it is expected that the neural networks of the intestines are very dynamic and at least some of their cells are lost due to normal attrition or disease. Nevertheless, we know very little about the mechanisms that maintain the nervous system of the gut in good functional order and the cell types that are likely to be mobilised to replace potential intestinal neural cell losses. In our studies we will use a range of experimental approaches to characterise the dynamic behaviour of neural cell networks of the gut and understand the biological mechanisms that control their maintenance and regeneration in adult life.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Elucidating RNA metabolism changes underlying the progressive neural cell biology of ALS
Funder: Wellcome Trust

Abstract: Growing evidence implicates abnormal RNA metabolism as a contributing factor to the pathobiology of amyotrophic lateral sclerosis (ALS), yet understanding remains limited in direct context of the human neurodegenerative condition. Addressing is expected to identify new disease mechanisms and therapeutic targets. I will integrate traditional and single-nuclei RNA sequencing to elucidate transcriptome-wide changes to RNA metabolism in clinically relevant post-mortem brain tissue and human induced pluripotent stem cell (hiPSC) models of ALS. Mechanistic follow-up of prioritised events will use established molecular biology, functional genomics and systems biology methods within hiPSC models. Key goals are to: • Define RNA metabolism changes in direct context of human ALS neuropathology: Molecules and networks will be characterised at region, cell and pseudo-temporal resolution. • Mechanistically dissect key RNA metabolism changes causing neural cell dysfunction: Priority will be understanding cause and consequence of non-canonical splicing reversed in ALS, and identifying intrinsic master regulators driving well-defined transcriptome signatures of motor neuron neurodegeneration. • Understand how familial ALS genetics converge on selective motor neuron vulnerability: Meta-analysing transcriptomes of perturbed single cells will functionally cluster familial ALS genes by induced cellular phenotypes. Taken together, fellowship findings will provide penetrating insights into basic neural cell dynamics relevant to ALS initiation and progression.

Lay abstract: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. It is rapidly progressing, universally fatal, and results from death of nerve cells responsible for movement. It affects 1 in 400 people and has no known cure. Disturbance of genetic ‘messages’ of RNA are always observed in ALS, and I aim to understand these changes at region, cell-type and temporal resolution in direct context of the human condition. To do so I will integrate state-of-the-art experimental and computational approaches with study of human post-mortem tissue and stem cell models. With this I will identify key RNA messages that change and contribute to ALS development, reveal master regulator genes whose altered activity actually initiates the RNA disturbances, and understand how RNA abnormalities in varied cell types (i.e. nerve or support cells) collectively conspire to cause motor neuron death. Together this will facilitate rational design of effective ALS treatments in future.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Computational Modelling and Inference of Neurodegenerative Disease Propagation
Funder: Wellcome Trust

Abstract: This project uses computational modelling, machine learning, and big-data analysis to address key unknowns on the biology of neurodegenerative disease: when and where it starts; how it spreads over the brain (“propagates”); how it varies among diseases, subtypes, and individuals; how risk factors influence mechanisms. Current models linking imaging and other clinical data to propagation mechanisms are crude, and evaluation remains largely qualitative. The project introduces a powerful Bayesian inference framework, accounting for uncertainties throughout the data-processing pipeline, to enable robust evidence quantification of new and detailed computational models of disease propagation. The approach demands a rethink of contributing technologies. First, we unravel patient heterogeneity, which confounds propagation-model evaluation, through a new generation of data-driven disease progression models that identify fine-grained disease subtypes characterised by temporal trajectory of multi-modal biomarkers. Second, propagation models use brain connectome estimates and are confounded by high connection-error rates. We establish a new probabilistic connectomics paradigm that quantifies likelihoods of false positive and negative connections enabling models to mitigate their inevitable presence. We use the framework to provide the first truly quantitative evaluation of propagation models against state-of-the-art data sets leading to fundamental new insights on the mechanisms of pathology propagation in neurodegenerative diseases.

Lay abstract: Neurodegenerative disease may be the biggest challenge facing 21st Century healthcare. Delaying Alzheimer’s onset by five years would relieve untold suffering and save £10B annually in the UK. This may come from a) treatments that slow disease (none are yet proven), or b) avoiding risk-associated behaviour. Both require deeper understanding of disease initiation and progression. Molecular biology has provided fundamental insights into how abnormal toxic proteins appear and propagate killing brain cells and disrupting cognitive ability. However, conflicting theories on the driving mechanisms remain, with little prospect of resolution from bottom-up molecular investigation.I propose a complementary top-down viewpoint using machine learning to infer underlying disease processes from macroscopic pathological patterns observed in imaging data from large patient groups. This uniquely reveals the variability among patients supporting personalized prevention and treatment. Ultimately, it brings computational models to the forefront of understanding and managing neurodegeneration, cf. computational fluid-dynamics in weather prediction.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Control of body temperature: molecular basis of sensory and effector mechanisms
Funder: Wellcome Trust

Abstract: The overall aim will be to determine the mechanisms that mammals use to sense and to maintain their body temperature. 1) How do mammals sense warmth and cold? In work leading up to this proposal we have found that TRPM2 is a novel warmth-sensitive mechanism in somatosensory neurons. We will extend this work by (i) studying the properties of warmth-sensitive nerve fibres in vivo; (ii) determining the molecular basis of the sensation of strong cold (iii) determining the critical thermal sensors which detect and defend core body temperature in thermo-regulatory neurons of the hypothalamus. 2) How do mammals maintain their body temperature in the face of thermal challenges? The warmth-sensitive TRPM2 ion channel and the novel cold-sensitive mechanism are expressed in autonomic neurons. We will use single-neuron imaging in vitro and in vivo, combined with studies of autonomically modulated functions such as vasoconstriction and sweating, to determine the role of these novel mechanisms in the control of body temperature. 3) How is body temperature elevated in fever? We will determine how central thermostatic mechanisms are modulated by pyrogens such as PGE2 to cause fever.

Lay abstract: How do we sense warmth and cold? Perhaps surprisingly, the molecular basis of how we sense ambient warm temperatures was unknown until recently. Our group showed that an ion channel called TRPM2, which spans nerve cell membranes and so regulates electrical activity in sensory neurons, directly senses warmth. We now want to elucidate in a similar way the mechanism responsible for detecting strong cold, and the mechanisms by which thermo-sensitive neurons in the brain respond to warmth so as to maintain bodily temperature. How do we expend or conserve heat so as to maintain bodily temperature in the face of thermal challenges? Both the TRPM2 warmth-sensitive mechanism and the unknown cold-sensitive mechanism are (surprisingly) present in sympathetic neurons, which are known to regulate body temperature. What is the function of these novel sensory mechanisms? Finally, how are brain thermo-sensitive mechanisms in the brain modulated to cause fever? We will investigate the effect of factors known to cause fever – do these act on the same warmth-sensitive mechanisms as we use to maintain normal body temperature, or are different mechanisms involved? Discovering the molecular mechanisms involved in fever may aid in developing drugs to control pathological fever states.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: THE MS AND PD TISSUE BANK AT IMPERIAL COLLEGE LONDON
Funder: MS Society

Abstract: The UK MS and PD Tissue Banks were set up at Imperial College in 1998 and 2002 respectively and have operated as a single bank since 2009. During this time, we have obtained informed consent for tissue donation from 11,794 people in total (3,430 with MS, 2,709 with PD and 5,655 controls), making it the largest such donor scheme in the UK and Europe. We have retrieved 2,018 brains (701 MS, 1077 PD and 240 controls) since 1998 and the current accrual rate is approximately 170-180 per annum. Tissue has been supplied to over 500 requests worldwide and we receive 50-60 new requests every year. This has resulted in over 200 peer reviewed publications and many projects are being translated into clinical benefit. The primary mission of the Tissue Bank at Imperial College has always been to facilitate research discoveries relevant to improving care, prevention or cure in MS and PD by making wellcharacterised human material of the highest quality available to the research community around the world. Further details about the existing operation can be obtained from our Annual Report to the MS Society and Parkinson’s UK. Here we outline our strategy for the next 5 years to maintain the Tissue Bank as one of the leading resources for research on MS and PD and to ensure maximum scientific value of the tissues.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL