NIHRDataInsights/HRCSData huggingface dataset:
Title: Isolation of neural stem cells from the postnatal brain for autologous cell therapy of demyelinating disorders in infants
Funder: Action Medical Research

Abstract: Background Leukodystrophies are a group of rare, genetic neurological disorders which affect the growth or maintenance of the myelin sheath that protects and insulates nerve fibres in the brain. The most common symptom of a leukodystrophy is a gradual decline in an infant or child who previously appeared well. There may be a progressive loss of muscle tone, movement, speech, vision and hearing, often accompanied by arrested intellectual and physical development. Leukodystrophies affect two out of every 100,000 babies born and there are currently no treatments for these devastating and invariably fatal disorders. However, encouraging results have been obtained with cell transplantation where neural stem cells (cells found in specialised areas of the brain that can develop into many different types of cells) are transplanted into the brain and begin to produce new myelin. These researchers plan to investigate different ways of carrying out this type of treatment. The research project So far, experimental transplantation studies have used donor neural stem cells. Unfortunately, the recipient's immune system recognises these cells as 'foreign' and tries to reject them unless aggressive treatment is given to suppress the immune system. In this project the researchers will test a new method that allows them to easily and safely collect neural stem cells from rat and mouse models of leukodystrophies. They will then investigate if these cells can be transplanted back into affected brain tissue where they can make new and healthy myelin. Using an individual's own stem cells for transplantation removes the risk of rejection and the need to suppress the immune system. If successful, this project could lead to work in more clinically-relevant settings with the ultimate goal of establishing new treatments for babies and children with these life-limiting disorders.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Optogenetically-controlled restoration of muscle function in ALS model mice using engrafted ES-derived motor neurons
Funder: Motor Neurone Disease Association

Abstract: Motor neuron disease (MND) results in the loss of the nerve cells, known as motor neurons (MNs), that connect the brain to muscles and thus control movement. The resulting muscle weakness and eventual paralysis can affect all muscles within the body, including those required for breathing. Once the disease starts, it cannot be slowed down or reversed as no effective disease-modifying therapy currently exists for MND. We have recently developed a novel strategy that can replace lost motor neurons, by transplantation of motor neurons obtained from embryonic stem cells (ESC-MNs) into nerves that control specific muscles. Importantly, these ESC-MNs produce a light-sensor, called channelrhodopsin-2 (ChR-2), which allows us to control their activity using pulses of light. This in turn enables fine control of the muscles that these ESC-MNs reinnervate allowing them to contract and produce muscle force. We have developed this technique in a nerve injury model in normal mice, however, we now have preliminary evidence that the same approach can be applied to the SOD1G93A mouse model of MND/ALS. The goals of this project, therefore, are to refine this strategy (including development of an implantable optical stimulation device) and to fully evaluate the extent to which muscle function can be restored in SOD1G93A mice that better model MND. Within a few years, we hope that this strategy could be used in MND patients to restore function, particularly of the diaphragm muscle, which is responsible for breathing, thereby enabling patients to breathe without the need for a mechanical ventilator. Ultimately, however, this technique could be used to control more complex motor functions.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Zebrafish C9orf72 loss of function models of ALS
Funder: Motor Neurone Disease Association

Abstract: Recently defects in a gene named C9orf72 were identified in families who develop MND. Analysis of a large number of patients revealed that C9orf72 is actually the most prevalent cause of MND that is currently known, accounting for approximately 1 in 10 of all cases of MND. The objectives of this project are to try and understand the function of the C9orf72 gene, and to determine how defects in this gene lead to the development of MND. The first aim is to make a zebrafish model for studying C9orf72. This will allow us to learn about the jobs normally carried out by C9orf72 in the brain and spinal cord, and to determine the effect of defective C9orf72 in the context of an animal model. The second aim is based on some exciting new evidence from recent experiments in Sheffield that C9orf72 regulates a process called autophagy, which comes from the Greek phrase meaning “self-eating”. Autophagy is the way that cells are able to break down damaged components. It is suspected that if autophagy stops working efficiently then cells start to accumulate damaged materials, and this is seen in several brain diseases including MND. We propose to directly test whether C9orf72 defects associated with ALS lead to disruption of autophagy in our zebrafish model. This project will be conducted in the Sheffield Institute for Translational Neuroscience, where our research is focused on the underlying causes of diseases in order to gain insight into what is happening inside the bodies of patients. By identifying faulty pathways in animal models and patient samples we can start to design targeted treatments and develop new ways of diagnosing disease. Our pilot studies suggest that we may have our first clue that autophagy could be targeted as a new treatment for patients with MND. It is only by testing this treatment in animal models, such as the one we will develop in this project, that we can tell whether the treatment stands a good chance of working in human patients. For instance it might not stop or reverse the symptoms of MND, but it may slow them down or make them milder.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: An investigation of the roles of TDP-43 and FUS in regulation of the neuronal cytoskeleton in Amyotrophic Lateral Sclerosis
Funder: Motor Neurone Disease Association

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a form of motor neuron disease which causes progressive paralysis and eventual death. There is currently no effective treatment for this disease, which produces devastating consequences for the patients and their families. We have recently identified two genes which are mutated, and therefore misfunction, to cause ALS. Our research will unravel the way in which these two genes, TDP43 and FUS, normally function in neurons, and how these functions can go wrong to cause ALS. These genes code for proteins which regulate normal processes in cells, including the function of RNA molecules. Our project will test the idea that the misfunction of these proteins affects RNAs that code for key structural components of cells, called the cytoskeleton. Our study will be undertaken mainly using an animal model, namely the chick embryo, in which we would use experimental approaches in the embryo as well as motor neurons in culture. We will discover whether particular cytoskeletal components are abnormal in neurons carrying mutant ALS proteins, and discover whether they can grow normally and make normal connections with muscles. By pinpointing precisely which aspects of the cytoskeleton are changed in ALS, we will pave the way for the future development of therapies. For example, drugs might be developed which would restore the function of faulty cytoskeletal molecules identified by us to be regulated by TDP43 and FUS


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Using semirational design and single molecule imaging to generate antagonists of alpha-synuclein and understand their mechanism of action.
Funder: Parkinson's UK

Abstract: We will harness semi-rational design and library screening using Protein-fragment Complementation to develop peptide antagonists of alpha-synuclein, the pathogenic agent responsible for Parkinson's disease. The in vivo 'Protein-fragment Complementation Assay' (PCA) selection system is multiplexed, generating effective peptides that reduce toxicity and confer cell survival. Antagonist efficacy in preventing amyloid formation will initially be assayed using ThioflavinT dye binding assay and electron microscopy. Antagonists will next be robustly characterised using a single molecule imaging technique known as 'Total Internal Reflectance Microscopy' (TIRFM) to visualise intermediate species populated when monomeric peptide progresses to large insoluble fibrils. These intermediates are considered to be the toxic species, and their formation be monitored by concomitantly undertaking 'MTT assays' to verify precisely which amyloid species confer toxicity. As previous drug design attempts have targeted insoluble fibrils, some have consequently increased toxic intermediate concentrations. Using TIRFM, both amyloid and antagonist will be labelled with differently coloured quantum dots (Qdots), meaning the mechanism of peptide antagonism can be directly evaluated. Specific questions to be addressed include: what is the toxic species? How do antagonists function? Which oligomeric species is populated due to inhibition? Can antagonists breakdown pre-formed amyloid in addition to preventing assembly? As a proof of concept we have very recently selected our first antagonist using PCA, demonstrating the feasibility of the system. Hence, by combining library design, screening and selection and real time imaging we will derive antagonists and gain mechanistic insight to permit further design of more effective inhibitors with combined active antagonist properties.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Activation of neuroinflammation by protein folding stress signaling pathways in Parkinson’s disease
Funder: Parkinson's UK

Abstract: Neuroinflammation in Parkinson's disease (PD) recruits microglia to damaged neurons. Microglia-dependent inflammation is a cause of neuronal death in PD. The origins of neuroinflammation in PD are poorly understood. One cause of PD is accumulation of protein aggregates in neurons. These aggregates poison the proteasomal protein degradation machinery, which has knock-on effects on protein folding in the endoplasmic reticulum (ER) leading to activation of ER stress signaling pathways known as the unfolded protein response (UPR). The UPR is activated in animal and cell culture models of PD. The UPR controls protein folding homeostasis, but upon severe or prolonged ER stress activates inflammatory and apoptotic cascades. The contribution of the UPR to neuroinflammation in neurodegenerative diseases has not been studied. We propose that the UPR activates inflammatory signaling pathways in diseased neurons and initiates neuroinflammation by promoting secretion of microglia-activating cytokines. Using Western blotting and quantitative reverse transcriptase PCRs we will monitor activation of the UPR and of inflammatory signaling molecules in in vitro differentiated neurons and primary neurons exposed to ER stress-inducing or PD mimetic drugs. We will study whether ER-stressed neurons secrete microglia-activating cytokines and whether media conditioned by ER-stressed neurons activate microglia. We will investigate whether inhibition of individual UPR signaling pathways by expressing dominant negative proteins or siRNAs mitigate inflammatory signaling and secretion of inflammatory cytokines and whether chemical chaperones ameliorate the inflammatory response of ER-stressed neurons. These experiments will establish whether UPR activation is a cause for neuroinflammation in PD and other neurodegenerative diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neuroprotective/behavioural effects of metabotropic glutamate receptors ligands in the lactacystein model of Parkinson’s disease
Funder: Parkinson's UK

Abstract: Dopaminergic cell loss in Parkinson's (PD) is associated with a number of downstream alterations in neuronal pathways, principally overactivity of glutamate pathways from the subthalamic nucleus. Such changes in glutamatergic projections not only trigger the principle clinical symptoms of PD but also may lead to further nigral neuronal loss due to excitotoxicity. The most promising approach to modulate glutamate activity has been through drugs that modulate metabotropic glutamate receptors (mGluRs) which have been shown to modulate behaviour and are neuroprotective. However, all studies so far have been carried out in acute PD models e.g.6-OHDA which are not progressive or demonstrate all neuropathological features of PD. Recently the direct nigral administration of the proteasome-inhibitor lactacystein has been used to produce a reliable progressive model of PD with protein deposition. In this model we demonstrated that the mGluR8 agonist DCPG was neuroprotective, demonstrating for the first time that in a progressive model of PD that when administered 7 days after the lactacystein lesioning DCPG is capable of rescuing dopaminergic neurons. This neuroprotection was associated with reduced alph-synuclein deposition and decreased innate inflammatory activation. This is the first time that mGluR ligands have been shown to affect protein deposition, however potential mechanisms are not known. This PhD is designed to test which other mGluR drugs are neuroprotective in the lactacystein model and assess by what mechanisms this occurs. We will also investigate which mGluR drugs can also modulate the behavioural signs of PD with the view of identifying candidate drug for clinical trials.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Investigating the functional significance of the interaction between PINK1 and mortalin – two genes implicated in Parkinson’ s disease.
Funder: Parkinson's UK

Abstract: Parkinson's Disease (PD) is a common neurodegenerative disorder with no known cure. The robust identification of the molecular mechanisms underlying this disease will greatly enhance our abilities to devise novel disease modifying treatments. Much of what we know about the molecular pathogenesis of the disease process in PD comes from the study of familial rare genetic forms of the disease. To date, genetic analysis has revealed several genes, which are implicated in the pathogenesis of PD, including PINK1, a mitochondrially targeted kinase implicated in neuroprotection. In order to gain further insight into the role of PINK1 in pathogenesis, we performed a screen to find new PINK1 interactors and have identified mortalin. Interestingly mortalin is also a mitochondrial protein and has already been implicated in PD. Mutations in the mortalin gene have been identified in PD patients and reduced levels of this protein have been reported in the brain tissue of postmortem PD brains. In this PhD fellowship application, we propose 1) To investigate further the genetics and expression levels of mortalin using our PD patient cohort; 2) To precisely dissect the interaction between PINK1 and mortalin and 3) To understand the pathophysiological relevance of this interaction, especially regarding mitochondrial function, known to be impaired in PD and neurodegeneration in general.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Role of fbxo7 in Parkinson's Disease
Funder: Parkinson's UK

Abstract: Recent work studying a group of Parkinson's disease patients has strikingly revealed that mutation in a previously unstudied gene termed Fbxo7, causes an early onset form of the disease. Other Fbx proteins a function as critical components of ubiquitin E3 ligases called Cullins. These play vital roles in regulating the ubiquitination and stability of target proteins. As the role of Fbxo7 is poorly understood, we will generate essential reagents (cDNAs, cell lines &amp; antibodies) to study Fbxo7. The first key goal would be to undertake mass-spectrometry interactor screens to identify which E3 ligase complex and substrates Fbxo7 interacts with. We will also generate knockin mice expressing an Fbx07 mutation that causes PD in humans. We also aim to obtain cell lines derived patients with Fbxo7 mutations. It would be important to understand whether Fbxo7 PD mutations affect assembly of Fbxo7 into E3 ligases components or interaction with cellular substrates. We would employ knockin mice and patient-derived cells to define what proteins Fbxo7 controls ubiquitination and stability. How mutations in Fbxo7 affect the ubiquitination and stability of these targets will also be a key question. The hope is that the information derived from this project provides new knowledge that is of relevance to understanding and treating PD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Tau and Parkinson's: Investigating mechanisms by which genetic variation at the microtubule associated protein tau (MAPT) locus may increase risk to PD
Funder: Parkinson's UK

Abstract: Meta-analysis by the PDGene forum places the microtubule associated protein tau (MAPT or tau) locus top of all genes associated with Parkinson's disease (PD). However, the mechanisms by which genetic variation at the MAPT locus affects susceptibility to Parkinson's remains unclear as PD is not a tauopathy. This proposal will investigate potential mechanisms in human dopaminergic neurons which may underlie two hypotheses which seek to explain the association of the MAPT H1 locus with Parkinson's. The first hypothesis is that the MAPT H1 locus is expressed at a higher level that H2 and that this is regulated by microRNA; the second hypothesis is that the overall expression levels are the same but the genetic association is explained by haplotype-specific expression of different MAPT isoforms We will screen the Oxford Discovery clinical cohort to identify individuals with an H1/H1; H1/H2; and H2/H2 genotype from whom we will generate induced pluripotent stem (iPS) cells differentiated into dopaminergic neurons. We will measure haplotype-specific expression of MAPT total expression and of splice variants and investigate if differences may be under the control of microRNAs. We will investigate the role of microRNAs which target tau in regulating axonal transport and dopamine homeostasis, two fundamental aspects of neuronal biology likely disrupted in PD. This project is of high significance in understanding the causes of PD. The genetic association of MAPT with a range of Parkinsonian disorders, including PD and the tauopathy movement disorders, argues for MAPT occupying a critical central role in shared mechanisms of neurodegeneration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: High-resolution structural ensembles to reveal the aggregation mechanism of alpha-synuclein: Toward an effective rational drug design
Funder: Parkinson's UK

Abstract: The aggregation and deposition in Lewy Bodies of alpha-synuclein (a-syn) are closely associated with Parkinson's disease (PD). Our limited understanding of the molecular mechanisms underlying these processes arises in no small part from the present lack of a detailed structural characterization of a-syn, as it is very challenging to apply standard methods of structural biology to this intrinsically disordered protein. In this project, we will initially aim at determining at high-resolution the conformational ensemble of a-syn by using a combination of nuclear magnetic resonance (NMR) and molecular dynamics (MD) methods. We will then determine also the structural ensembles of a series of familial PD mutations (A30P, E46K and A53T) of a-syn as well as the corresponding structural ensembles in the presence of molecules that are known to inhibit its aggregation propensity. We will thus identify the relationship between the conformational properties of the monomeric form of a-syn and its aggregation mechanism. This comparative study will provide the rational basis for the development of novel drugs for PD. This goal will be pursued by first individuating, through in silico screening of a large database of molecules, molecular candidates to target a-syn aggregation, which then will be tested in vitro by NMR and in vivo by using a C. elegans model of PD. Taken together, the results of this project will provide the molecular basis for the establishment of a rational strategy to develop effective therapeutic treatments for PD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Speaking with your hands in Parkinson’s: the role of co-speech gestures in communication
Funder: Parkinson's UK

Abstract: Parkinson's can impact enormously on speech communication. In healthy people, co-speech gestures can add meaning and emphasis to speech. There is some evidence that gestures are reduced by Parkinson's, alongside other motor problems Conversely, gestures might provide a means to compensate for poor speech in Parkinson's. To date, there has been very little research on the effect of Parkinson's on gestural communication. This PhD studentship will address three important questions. First, how does Parkinson's affect the spontaneous production of different types of co-speech gesture? We will compare video footage of people with Parkinson's and age-matched controls carrying out a description task. Gesture rate and type will be compared between groups. In addition, we will examine whether changes in gesture are associated with particular characteristics in the Parkinson's group. Second, are Parkinsonian co-speech gestures less well understood by other people? We will measure how gestures in clips obtained from the first study influences comprehension in young healthy participants, comparing their responses to the Parkinson's and control videos. Finally, we will investigate whether Parkinson's affects peoples' ability to comprehend co-speech gestures, by comparing a Parkinson's and control group on comprehension of the video clips obtained from the healthy participants in the second study. Overall, this project will contribute to the understanding of gestural communication in Parkinson's, increasing understanding of an important symptom and paving the way for potential interventions involving gesture. Our findings may also suggest how others can improve their communication with people with Parkinson's.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: NEUROLOGICAL