NIHRDataInsights/HRCSData huggingface dataset:
Title: The contribution of spinal inhibitory circuits to aberrant excitability in Amyotrophic Lateral Sclerosis
Funder: Wellcome Trust

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease targeting motoneurons, leading to paresis and death. Changes in spinal microcircuits have been suggested to be part of an early homeostatic response to preserve motor output, possibly involving substantial alterations at the level of premotor synapses. Supported by solid preliminary data, I hypothesize that changes in these circuits precede motoneuron degeneration, and thus propose to address these aims: (1) define early disruptions in connectivity to motoneurons in ALS and (2) determine the genetic profile of these abnormalities. I will characterize well-known spinal synaptic pathways such as Ia excitation, disynaptic reciprocal inhibition and pre-synaptic inhibition in wildtype mice and 2 different models of ALS (SOD1G93A and TDP-43-A315T). I will do this both in vitro, by using a novel isolated mature mouse spinal cord preparation, and in vivo by performing intracellular recordings of motoneurons and EMG recordings with chronically implanted multielectrode arrays. These experiments will be complemented with transcriptomic analysis using single-cell patch seq and laser capture microscopy to reveal if changes in specific spinal microcircuits are accompanied by changes in expression profile of motoneurons and interneurons. This project will reveal if early degeneration in ALS results in generalized circuit impairment.

Lay abstract: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by death of cells located in the spinal cord that control muscle function (motoneurons), resulting in weakness and death. Motoneurons form complex neuronal circuits with other cells in the spinal cord (interneurons) to ensure effective muscle contraction. Supported by preliminary data, I hypothesize that these circuits are affected in ALS and could contribute to motoneuron death. The aim of this project is to understand how such circuits are affected in ALS and how these abnormalities contribute to the disease. I will use two genetically modified mouse models with ALS-inducing human mutated genes, perform electrical recordings from motoneurons and characterize gene expression abnormalities both in interneurons and motoneurons. This project will reveal early alterations in specific circuits, which could shift our understanding of ALS and provide a mean for early diagnosis which could potentially lead to earlier and more efficient treatment.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the role of gut macrophages in mediating alpha-synuclein pathology in Parkinson’s disease
Funder: Wellcome Trust

Abstract: The gut-brain axis is at the heart of Parkinson’s disease (PD) etiology. Pathological alpha-synuclein accumulates early in the gut, potentially affecting the enteric nervous system (ENS) and spreads to the brain. However, we lack insights into how pathological alpha-synuclein affects ENS integrity and cellular mediators underlying their spread. Here, I propose to study the role of a unique subset of gut macrophages (gMacs), the ENS-gMacs, that coordinate neuronal function in their unique ENS niche. I hypothesize that ENS-gMacs critically dependent on LRRK2 for alpha-synuclein clearance. LRRK2 is a risk factor for PD, regulates alpha-synuclein clearance in macrophages and is highly enriched in ENS-gMacs compared to microglia and neurons. First, using state-of-the-art single cell RNA and in-situ sequencing techniques I will examine how ENS-gMacs and microglia become dysfunctional in PD mouse models. Second, using in vivo and in vitro tools, I will dissect whether mutant LRRK2 signaling in ENS-gMacs affects neuronal function and survival upon PD patient-derived pathological alpha-synuclein. Finally, I will investigate how ENS-gMacs contribute to alpha-synuclein pathology and spread. Insights obtained will create new avenues to study neuroimmune pathways along gut-brain axis for the future, as well as novel targets for early therapeutic interventions in PD.

Lay abstract: Our gut has its own unique immune cells that are vital for a healthy and functional gut nervous system. In Parkinson’s disease (PD), focus is being centered on the gut’s nervous system as we see early aggregation of toxic alpha-synuclein there to further ‘travel’ or spread to the brain, where it contributes to loss of specific nerve cells. This raises the question of how gut immune cells respond to toxic alpha-synuclein, contribute to gut dysfunction (constipation) and further toxic spreading in PD. I will study how dysfunctional immune cells in the nervous systems of the gut and brain contribute to toxic alpha-synuclein progression. I will use mouse models of PD to study the role of these immune cells and cutting-edge tools to examine how and when these cells become dysfunctional. Targeting these cells and interactions with neurons could alter the course of PD by preventing early alpha-synuclein pathology and spread.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Next-generation diffusion MRI: Illuminating the black holes of the brain
Funder: Wellcome Trust

Abstract: A major challenge in establishing novel therapeutics for neurological diseases is the assessment of tissue health. The inaccessibility of the brain for biopsy has motivated the development of novel technologies, with diffusion Magnetic Resonance Imaging (MRI) emerging as one of the most promising techniques to non-invasively assess brain tissue. Diffusion MRI generates images sensitive to the microscopic motions of water within and around cells. It has demonstrated considerable potential to identify novel biomarkers in a number of neurological diseases.Despite this promise, conventional diffusion MRI methods have failed to access certain key brain regions. In these regions, rapid signal-decay (short-T2) leads to low-quality images with the appearance of ‘black holes’. I propose to establish an imaging platform that enables us to assess tissue health in these previously inaccessible regions. I will achieve this using a little-known but powerful technique, ‘steady-state diffusion’.Building on a framework I have recently developed, I will: 1. Transform steady-state diffusion images into those with clear biological interpretation. 2. Enable in vivo use by overcoming its extreme motion-sensitivity. 3. Reduce examination times by integrating the estimation of signal dependencies. Utilising this platform, I will investigate the substantia nigra, a black hole brain region of critical importance in Parkinson’s disease.

Lay abstract: Magnetic resonance imaging (MRI) provides us with many ways to image the brain without radiation or injections. One example is diffusion MRI, which allows us to generate images sensitive to the tiny random motions (diffusion) of water within and around cells. Many diseases change the environment where water diffuses. Diffusion MRI can detect this change, which we can use to assess brain health.Unfortunately, in many important brain regions the diffusion MRI signal disappears before we can make a measurement. These regions appear as dark ‘black holes’ in resulting images, preventing us from identifying disease-related changes.I will transform brain health assessment in these important brain regions, using a technique which rapidly captures the disappearing signal, ‘steady-state diffusion’. Currently, steady-state diffusion suffers from a series of challenges, severely restricting its use in living people and image interpretability. I will overcome these challenges, and investigate its potential in assessing Parkinson’s disease.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Identifying the Neural and Cognitive Contributors to Dizziness in Older Adults
Funder: Wellcome Trust

Abstract: Dizziness is common in older adults and is strongly associated with more frequent falls. Nonetheless, treating this condition represents a significant challenge as clinicians are often unable to identify a physical cause (and, thus, dizziness is ‘unexplained’). Pilot work implies that unexplained dizziness may stem from attempts to consciously process balance. However, a causal relationship has not been established. Further, the specific mechanisms through which conscious processing influences dizziness remain unknown. My goals are to (i) investigate whether conscious balance processing is causally associated with symptoms of unexplained dizziness, and (ii) identify the neuro-cognitive mechanism/s that likely underpin such a relationship. I will conduct a programme of research to test the hypothesis that conscious balance processing influences dizziness through a hypersensitivity to sensory input, in that even minor fluctuations within ‘normal’ bounds are perceived as unsteadiness. I will measure symptoms of dizziness and assess sensory processing during baseline balance conditions, as well as during experimental manipulations that either promote or prevent conscious balance processing. Data will be compared between older adults with unexplained dizziness and age-matched controls. This work will advance our understanding of how neuro-cognitive factors contribute to dizziness, informing the development of novel therapies that target these mechanisms.

Lay abstract: Older adults often report feelings of dizziness. Dizziness can disrupt balance and increase the likelihood of a fall occurring. Rather than having a clear physical cause, preliminary research suggests that dizziness in older adults may often be caused by psychological factors; specifically, thinking about one’s balance more than is necessary or helpful. However, it is not known how such ‘over-thinking’ influences dizziness. One idea is that this may disrupt the subconscious brain processes that typically control balance. I propose to measure symptoms of dizziness and assess brain activity during baseline conditions of balance, as well as during experimental manipulations that either promote or prevent over-thinking about balance. Data will be compared between dizzy older adults and older adults without dizziness complaints. This work will advance our understanding of the psychological factors that contribute to dizziness in older adults. This will inform the development of novel therapies that target these mechanisms.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Deciphering the brainstem circadian clock: intrinsic circadian control over ingestive functions by the dorsal vagal complex in health and obesity
Funder: Wellcome Trust

Abstract: Daily partitioning of feeding is crucial for well-being and survival, but neuronal mechanisms underlying this process remain poorly understood. The dysregulation of circadian rhythmicity seen in the modern 24/7 society leads to obesity, cardio-vascular problems, metabolic syndrome and some kinds of cancer, constituting a major public health burden. Recently, we found that a brainstem satiety centre – the dorsal vagal complex (DVC) harvests exceptionally robust timekeeping properties, which are additionally sensitive to diet. This projects aims at understanding the neurochemical identity of the DVC clock, its possible ways of entrainment and role in physiology and obesity. These goals will be achieved with the use of a unique combination of tools, including cutting-edge molecular techniques (single-cell RNAseq and RNAscope) and real time monitoring of bioluminescence reporters. Additionally, we will combine optogenetic tools to stimulate vagal afferents, with multi-channel electrophysiology ex vivo and behavioural monitoring of food and water intake. Moreover, the output of the brainstem clock will be measured with the working brainstem-gut model. Results of this project have a potential to elucidate neural mechanisms of daily rhythms in satiety, but also possess clear translational clinical values for a restoration of circadian rhythmicity in obese patients by timed vagus nerve stimulations.

Lay abstract: Feeding constitutes one of the most critical behaviours for survival and both the amount of food consumed and its timing are crucial for the maintenance of homeostasis. Here with the use of a unique combination of research techniques, we propose to investigate neuronal mechanisms of the daily control of satiety and their disturbances in obesity. Additionally, we aim to restore proper circadian rhythmicity in obese rodents by timed stimulations of vagus nerve, which could illuminate and inform clinical and chronotherapeutic treatment of obesity.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Investigating a novel role of C9orf72 at the presynapse and its involvement in FTD/ALS.
Funder: Alzheimer's Research UK

Abstract: In the brain, approximately 100 billion nerve cells (neurons) allow us to think, remember, see, hear, speak etc. Neurons talk to each other at connections, called synapses, using a process called neurotransmission. Communication between neurons is important for brain functions such as memory. In dementia synapses are lost and this disrupts the communication between neurons. When the communication is lost for too long the neurons will eventually die. This causes the clinical features of dementia. In this project we want to investigate what causes synapses to disappear in a form of dementia called frontotemporal dementia (FTD). We are specifically interested in a process called autophagy, or “self-eating”, which is a way for the neurons to get rid of damaged components. It is called self-eating because the cell eats damaged parts of itself. The reason we are interested in autophagy is because genetic studies have shown that a gene that regulates this process is defective in FTD. We think that malfunction of autophagy causes damage to the synapses so they misbehave and eventually break down. If we can confirm this we will be one step closer toward a treatment for dementia.

Lay abstract: In the brain, approximately 100 billion nerve cells (neurons) allow us to think, remember, see, hear, speak etc. Neurons talk to each other at connections, called synapses, using a process called neurotransmission. Communication between neurons is important for brain functions such as memory. In dementia synapses are lost and this disrupts the communication between neurons. When the communication is lost for too long the neurons will eventually die. This causes the clinical features of dementia. In this project we want to investigate what causes synapses to disappear in a form of dementia called frontotemporal dementia (FTD). We are specifically interested in a process called autophagy, or “self-eating”, which is a way for the neurons to get rid of damaged components. It is called self-eating because the cell eats damaged parts of itself. The reason we are interested in autophagy is because genetic studies have shown that a gene that regulates this process is defective in FTD. We think that malfunction of autophagy causes damage to the synapses so they misbehave and eventually break down. If we can confirm this we will be one step closer toward a treatment for dementia.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neuronal senescence as a contributory mechanism to dementia
Funder: Alzheimer's Research UK

Abstract: Markers of dementia, such as tangles and plaques that characterise Alzheimer’s, do not explain all dementia, and treatments aimed at them have been unsuccessful. This suggests other processes contribute to dementia. Senescent cells, sometimes called zombie cells, are persistently damaged cells, often because of damage to their DNA, which carries all the instructions for the cell. These cells remain alive, but they do not carry out their normal functions. Additionally, they produce factors that damage nearby cells and cause inflammation. Zombie cells are described in other tissues and diseases, and there are drug treatments aimed at them. However, their role in dementia is not understood. Using brain tissue samples from the Cognitive Function and Ageing Study, we plan to identify senescent nerve cells in the brain and determine how they relate to dementia. To determine how senescence causes damage, we will isolate nerve cells with and without markers of senescence from the same cases, and investigate effects on the cells by determining differences in the gene messages present. This will provide greater understanding of how senescence contributes to dementia and identify specific ways in which senescence affects nerve cells, which may lead us to new approaches to target zombie cells.

Lay abstract: Markers of dementia, such as tangles and plaques that characterise Alzheimer’s, do not explain all dementia, and treatments aimed at them have been unsuccessful. This suggests other processes contribute to dementia. Senescent cells, sometimes called zombie cells, are persistently damaged cells, often because of damage to their DNA, which carries all the instructions for the cell. These cells remain alive, but they do not carry out their normal functions. Additionally, they produce factors that damage nearby cells and cause inflammation. Zombie cells are described in other tissues and diseases, and there are drug treatments aimed at them. However, their role in dementia is not understood. Using brain tissue samples from the Cognitive Function and Ageing Study, we plan to identify senescent nerve cells in the brain and determine how they relate to dementia. To determine how senescence causes damage, we will isolate nerve cells with and without markers of senescence from the same cases, and investigate effects on the cells by determining differences in the gene messages present. This will provide greater understanding of how senescence contributes to dementia and identify specific ways in which senescence affects nerve cells, which may lead us to new approaches to target zombie cells.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The therapeutic effect of PGC1α at advanced stages of Alzheimer's disease in animal models of amyloid and tau pathology
Funder: Dunhill Medical Trust

Abstract: The PPARγ coactivator-1α (PGC-1α) is a transcriptional regulator that controls major metabolic functions through the co-activation of PPARγ and other transcription factors. Our previous studies indicate that PGC-1α decreases the secretion of Aβ in cell culture and its levels are reduced in the brain of Alzheimer’s disease (AD) patients. In addition, we recently reported that PGC-1α gene delivery using viral vectors in a model of amyloidosis at pre-symptomatic stages of AD resulted in decreased Aβ plaques, neuronal loss and improved memory. In this proposal we aim to investigate whether PGC-1α effects on Aβ reduction and neuroprotection also occur at advanced stages of the disease and if reduces neurofibrillary tangle formation in tau transgenic mice as well. Furthermore, whether coexpression with necdin, a potent PGC-1α stabilizer, will potentiate these effects. The results of this project will demonstrate whether modulation of PGC-1α has real therapeutic potential at severe stages of AD.

Lay abstract: In this project our goal is to assess whether PPARγ coactivator-1α (PGC-1α), a protein that has a potential role regulating expression of genes involved in type 2 diabetes could be protective against Alzheimer’s disease (AD) at late stages of the disease. Our published results show that PGC-1α levels are reduced in AD patients. In addition, injection of PGC1α gene in an animal model of AD at early stages of the disease reduced brain pathology, decreased neuronal loss and improved memory. In this project, we aim to use PGC1α overexpression as genetic therapy for AD by injecting it in the brain of two different animal models of AD at older age and investigating the reduction of the main components of AD pathology; the Aβ plaques, the neurofibrillary tangles and loss of neurons. We believe that if this therapy proves to be effective, it could be used to treat advanced AD patients.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Interplay between T cell immunity and innate neuroinflammation in primary Tauopathies
Funder: Alzheimer's Research UK

Abstract: Frontotemporal dementia (FTD) is the second most common form of dementia under the age of 65 and represents a diverse group of progressive neurodegenerative disorders characterized by behavioural and personality disturbances. Genetics and preliminary experimental studies suggest that accumulation of pathological Tau proteins in the brain of FTD patients could trigger a brain inflammatory response associated with brain infiltration of the lymphocyte T cells, which may contribute to promote disease progression through an impact on innate brain inflammation. However, the nature of such intricate brain-immune interactions in FTD remain poorly defined. The objectives of our project are to: Characterize brain-associated T cells in line with the resident brain immune cells microglia in the human disease, using post-mortem tissue from 93 patients who died from FTD compared to 50 non-demented people. Decipher the impact of T cell responses on the functional activation profile of microglia, using an in-house developed and well-characterized mouse model of FTD and validation studies in human samples. This study has the potential to unravel innovative and emerging aspects of the pathophysiology of Tauopathies, and identify new key pathways and markers of detrimental innate neuroinflammation and disease progression in such pathologies.

Lay abstract: Frontotemporal dementia (FTD) is the second most common form of dementia under the age of 65 and represents a diverse group of progressive neurodegenerative disorders characterized by behavioural and personality disturbances. Genetics and preliminary experimental studies suggest that accumulation of pathological Tau proteins in the brain of FTD patients could trigger a brain inflammatory response associated with brain infiltration of the lymphocyte T cells, which may contribute to promote disease progression through an impact on innate brain inflammation. However, the nature of such intricate brain-immune interactions in FTD remain poorly defined. The objectives of our project are to: Characterize brain-associated T cells in line with the resident brain immune cells microglia in the human disease, using post-mortem tissue from 93 patients who died from FTD compared to 50 non-demented people. Decipher the impact of T cell responses on the functional activation profile of microglia, using an in-house developed and well-characterized mouse model of FTD and validation studies in human samples. This study has the potential to unravel innovative and emerging aspects of the pathophysiology of Tauopathies, and identify new key pathways and markers of detrimental innate neuroinflammation and disease progression in such pathologies.

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