Florey Department of Neuroscience and Mental Health - Theses
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ItemThe Nature and Severity of Central Nervous System Dysfunction after Concussion in Contact Sport( 2019)Introduction. Traumatic brain injuries, including sports-related concussions, are a major public health concern. Although participation in sport brings with it many benefits, the potential risk of sustaining adverse injuries such as sports-related concussion is an escalating societal and ethical issue. The onset of short-lived impairment of central nervous system dysfunction in concussed athletes following a sport-related concussion can lead to complications if the condition is not recognised and removed from participation in sport in a timely manner. Rationale and Study aims. This series of studies aim to understand the nature and magnitude of head biomechanics, short-lived impairment of central nervous system (CNS) function, and clinical signs and symptoms associated with concussions and repetitive head impacts. More specifically, it is hypothesised that (i) the biomechanics of repetitive head impacts in amateur boxers, (ii) endorsement of symptoms, and performance on cognition and balance component scores immediately post-contest and, (iii) a decline in function on the King-Devick test, will be worse for boxers clinically classified with a concussion, be associated with high-risk for CNS injury circumstances, and be reflective of exposure to repetitive head impacts through exposure to repeat contests in the tournament. Method. Healthy male collegiate students (n = 376) between the ages of 18-34 years (M = 20.97, SD = 2.30) consented to participate in the Notre Dame Bengal Bouts amateur boxing tournament in 2012 and/or 2013. Boxers completed the Sports Concussion Assessment tool, Cogstate Brief Battery, and the King-Devick test prior to participation in any sparring and following each of the four elimination contests. A sample of boxers were also instrumented with X2 Biosystems headbands to monitor exposure to impacts during contests. Results. The results of this study support the hypothesis that in amateur boxers the number of head impacts, and the acceleration of those impacts are associated with the progress through the tournament, outcome of bouts, weight class, and concussion. However, there were no systematic differences in the number or magnitude of impacts between concussed and non-concussed boxers, although average rotational forces did show potential for the classification of concussed boxers. Symptom, cognition, and balance scores did not systematically change with multiple assessments nor with repeat exposure to head blows further into the tournament, however, symptom component scores were sensitive to and worse for boxers classified on performance factors representative of high-risk for CNS injury, such as sustaining a concussion, receiving a standing eight-count, and losing a contest. The cognitive component was successful in identifying concussed boxers from non-concussed boxers. But there were no meaningful differences on the balance component clinically relevant to the assessment of concussion-related changes. The King-Devick test was largely not sensitive to concussion in the context of amateur boxing and unable to appropriately classify most concussed boxers. Conclusion. This study offers guidance on the measures which provide the best predictive power for the classification of central nervous system dysfunction following a sport-related concussion and adds to the literature on repetitive head impacts. Though innovative, further study of the biomechanics of concussive head injury, amateur boxers, and the use of screening tools are warranted.
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ItemInvestigating the role of Tyro3 in the central nervous system( 2020)One of the more remarkable aspects of myelination is the relationship between axon diameter and the correlating myelin thickness, whereby larger axons are ensheathed with more myelin. However, key regulators of myelin thickness in the CNS remain elusive. Previously, it was shown that that the tyrosine kinase receptor, Tyro3, is a key mechanistic component involved in controlling myelin thickness in the optic nerves of adult mice. Moreover, provision of the Tyro3 ligand, Gas6, dramatically increases clinical outcomes in a demyelinating mouse model. Tyro3 ligand provision also increased the corresponding total amount of myelin produced by myelinating oligodendrocytes in vitro. In addition, the promyelinating effects of Gas6 in vitro were lost when oligodendrocytes were devoid of Tyro3, suggesting the myelinating effect of Gas6 is up oligodendrocytes and is mediated by Tyro3. This thesis aims to further investigate the myelin regulatory role of Tyro3, firstly by assessing myelin thickness and oligodendrocyte maturation in a separate white matter tract in adult mice, the corpus callosum. Furthermore, this study aims to investigate the role of Tyro3 in demyelination and remyelination using the cuprizone induced, demyelinating mouse model. In addition, this study looks to identify the intracellular pathways in which Tyro3 and Gas6 regulate myelination in mouse oligodendrocytes. Finally, this study aims to understand how a nervous system devoid of Tyro3 functions by investigating action potential conduction in visual evoked potentials and compound action potentials. This research project shows that Tyro3 is a critical regulator of adult mouse myelin thickness, and that its expression is protective during demyelination and acts as a positive regulator of remyelination in the corpus callosum. Importantly, hypomyelination in the absence of Tyro3 occurred without alterations to oligodendrocyte maturation or mature oligodendrocyte density during the myelin establishment processes. In addition, although demyelination was more severe in the Tyro3 KO mice, microglial activation was normal. However, I was unable to identify an intracellular pathway in which Gas6 and Tyro3 may regulate myelin synthesis in mouse oligodendrocytes. Furthermore, the previously reported, promyelinating effects of Gas6 was not recapitulated when oligodendrocytes were grown on synthetic nanofibers rather than live neurons. These results suggest that the promyelinating effects of Gas6 could potentially be indirect and through neurons. Moreover, this study finds that in the absence of Tyro3, myelin loop arrangement at the node of Ranvier is significantly more disrupted than that of WT mice. However, the hypomyelinated and abnormal paranodal loop phenotype of the Tyro3 KO mice did not alter action potential conduction in the optic nerve or corpus callosum. To expand upon this, when the myelin structural parameters of Tyro3 deficient mice were placed within a synthetic action potential conduction model, a significant decrease in conduction velocities was observed in a single axon; however, it was lost when 400 axons were modelled as a myelinated tract. Finally, I show that in the absence of Tyro3, retinal function is significantly decreased, with fewer retinal ganglion cells present and a significant decrease in retinal ganglion cell dendritic density.
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ItemThe Microbiome-Gut-Brain Axis in Huntington's Disease( 2020)Huntington’s disease (HD) is progressive neurodegenerative disorder caused by the abnormal trinucleotide repeat expansion in the Huntingtin gene that is expressed throughout the brain and the body. Despite being a monogenic disease, patients show a range of central and peripheral symptoms with complex pathogenesis. Whilst the focus of much research has been on the cognitive, psychiatric and motor symptoms of HD, the extent of peripheral pathologies and its potential impact on the central symptoms has been less intensely explored. The microbiome-gut-brain axis represents the bidirectional communication between the brain and the trillions of microorganisms in the gut, whose collective genome is known as the gut microbiome. The role of the gut microbiome in modulating brain health and behaviour has been widely documented. Importantly, recent evidences have highlighted its regulatory role on the small RNA expression in the brain. Gut dysbiosis (imbalance of the gut microbiome) has been reported in a number of neurological diseases, implicating altered communication between the gut microbiome and the brain in these diseases. Hence, this body of work aimed to investigate the microbiome-gut-brain axis and its role in the pathogenesis of HD using the R6/1 transgenic mouse model. This study, first, established a dysregulation of brain miRNAs expression in the R6/1 HD mice at 12 weeks of age, prior to overt motor symptoms. At that age, we also presented the first evidence of gut dysbiosis in Huntington’s disease, coinciding with impairment with weight gain despite higher food intake. We then extended those findings by profiling the R6/1 HD gut microbiome from 4 to 12 weeks of age, representing young and adult stage of life, to pinpoint the age at which gut dysbiosis occurs in these mice, as well as to determine the changes in the gut microbiome function. In conjunction with this, plasma metabolomics was performed at 12 weeks of age to ascertain potential effects of gut dysbiosis on the plasma metabolome profile given that microbial-derived metabolites could cross the blood-brain-barrier and may regulate brain miRNA expression. Overall, we found significant gut dysbiosis as well as perturbation of the gut microbiome function in R6/1 HD mice at 12 weeks of age and not at earlier time points. Profiling of the plasma metabolome revealed no major alterations in R6/1 HD mice when compared to their wild-type littermates at 12 weeks of age. Multi-omics integration analysis revealed some novel correlations between the gut microbiome composition and the plasma metabolome profile. However, given the lack of alterations in the microbial-derived short-chain fatty acids in the blood of R6/1 HD mice, there is no strong evidence to support the role of gut dysbiosis in partially regulating striatal miRNA expression in addition to the HD gene mutation effect at 12 weeks of age. Collectively, this thesis provided new insights into the microbiome-gut-brain axis in HD, especially during the period prior to the manifestations of overt central symptoms of HD. Importantly, the work presented here highlights the gut microbiome as a potential avenue for therapeutic interventions which may be beneficial in managing the disease in gene positive individuals.
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ItemGenetic and pharmacological targeting of Heat shock protein 72 (Hsp72) in the 5xFAD*Tg30 mouse model of Alzheimer’s disease( 2020)The impact of Alzheimer’s disease (AD) is profound. In Australia, around 460,000 patients have dementia, AD being the most common form. An estimated 1.2 million people are involved in their care and it is the second leading cause of death. It is difficult to provide statistics purely on AD due to the difficulty in diagnosis, but an estimated 70% of dementia cases are AD (322,000 patients) (Dementia Australia 2018). Overexpression of the cytoprotective Heat Shock Protein 72 (Hsp72) is currently under investigation as a potential therapeutic option for prevention and treatment of AD due to its many protective mechanisms. The series of projects in this thesis aim to better understand the effects of upregulating Hsp72 in relation to behaviour, cognition and metabolism in a mouse model of AD. The aim of the first study was to replicate and extend on the characterisation of a recently developed mouse model of AD. The mutant 5xFAD (overexpressing human APP and Presenilin-1) was crossed with Tg30 (overexpressing tau) to produce 5xFAD*Tg30 mice and investigate the effects of tau accumulation in the presence of amyloid pathology, which closely resembles human AD. A comprehensive battery of behavioural and physiological tests were performed to observe cognitive and physical decline over time, between 3-8 months of age. In agreement with one previous report (Heraud et.al 2014), we observed a decline in Rotarod performance from 6 months onwards compared with wildtype control (WT). While we noted a decrease in spatial awareness and memory (Morris water maze) and significant genotype differences in anxiety-like behaviour (large open field) by 8 months, memory function (Y-maze) and novel object recognition were not significantly affected. The 5xFAD*Tg30 mice had a 40% decrease in survival by 10 months of age. Additionally, 5xFAD*Tg30 mice were smaller, with a significant difference in body weight, tibialis anterior skeletal muscle weight and tibia length. Our results successfully reproduced aspects of the previously published description of this model (Heraud et.al 2014), while adding further additional characterisation of the model. This initial characterisation study demonstrated that the model develops many aspects associated with AD including frailty, early death and initiation of cognitive decline to complement the previously described AD-like brain pathology, specifically the presence of amyloid-beta pathology with tau accumulation and neurofibrillary tangle (NFT) development, found in this model (Heraud et.al 2014). Hsp72 has been shown to play a cytoprotective role in AD- related research by inhibiting amyloid-beta oligomerization, enhancing its clearance, restoring tau homeostasis and inhibiting neuronal apoptosis. Hence, the aim of the second study was to genetically overexpress Hsp72 and study its effects on the 5xFAD*Tg30 mouse model of AD. As in the first study, we crossed 5xFAD and Tg30 mice, to create the double transgenic, 5xFAD*Tg30, then crossed the double transgenic mice with Hsp72 overexpressing transgenic mice (Hsp72 Tg) to create the triple transgenic, 5xFAD*Tg30*Hsp72Tg. BGP -15 is a compound described to be a co-inducer of Hsp72, and therefore, our third study hypothesized that pharmacologically activating Hsp72 with this compound may be advantageous in preventing or delaying AD progression and associated pathology. 5xFAD*Tg30 mice were treated with BGP-15 or vehicle in their drinking water in a randomised and blinded study in both male and female mice from the ages of 2-10months. A comprehensive battery of behavioural and metabolic tests was conducted for both the second and third studies, and results compared to littermate WT mice. We observed significant declines in Rotarod, Y-Maze and Novel Object performance and increased seizure activity in the 5xFAD*Tg30 mice compared to wildtype, however neither Hsp72 overexpression (study 2) nor BGP-15 treatment (study 3) rescued this decline. Hsp72 overexpression was partially effective in maintaining lean mass in male mice and improved performance on the elevated plus maze. In males there was a 38% decrease in survival rates by 10months of age in the 5xFAD*Tg30 mice, which was improved by BGP-15 treatment to only a 14% loss (p=0.07). In conclusion, BGP-15 may improve survival rates in a gender specific manner (male), while overexpression of Hsp72 leads to maintenance of lean mass in male 5xFAD*Tg30 mice. Both avenues used to target Hsp72 were insufficient, however, to protect against the observed cognitive deficits in the model.
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ItemFunctional and structural brain networks during epileptic spikes in human brain( 2020)Accurate localisation of the brain region responsible for the seizure onset is a critical step for refractory epilepsy patients to gain access to surgical treatment. In this work, EEG, functional MRI and diffusion-weighted MRI were used to enhance the current understanding of functional and structural properties of brain networks involved in epileptic activity in patients with refractory focal epilepsy. The findings of the studies included in this thesis support the view that epilepsy is a network disorder, and epileptic activity is organised in a complex network. This work showed that results from simultaneous EEG-fMRI studies can have a critical impact on patient management, including influencing the decision for targeted surgical resection, with good subsequent seizure outcomes. Preforming EEG-fMRI studies in patients with frequent spikes during inpatient video-EEG monitoring, while on reduced or withdrawn antiepileptic medications, may lead to a much higher proportion of successful cases. Similarly, automatic spike detection method can improve detection of epileptic spikes in scalp EEG recordings, significantly shorten the analysis time, and enhance the statistical power of EEG-fMRI analysis, revealing additional elements of the patient’s epileptic networks. This work proved that the addition of spike variability information into standard fMRI analysis of the EEG-fMRI data allows for better localisation of the origin of epileptic activity and its spread across the network. In addition, investigating the structural connections that may underlie functional networks can enhance the current understanding of the propagation pathways used by epileptic activity. This work demonstrated the utility of advanced analysis methods in the investigation of refractory epilepsy. Advanced neuroimaging techniques can better localise the epileptic onset and propagation of epileptic activity. Combination of information from different diagnostic modalities bridges the gap between neurophysiology (EEG) and imaging (MRI) of epilepsy and may be a useful adjunct to the presurgical assessment of refractory epilepsy.
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ItemTargeting HCN4 channels in epilepsy( 2020)Epilepsy is a prevalent neurological disorder that affects around 65 million people worldwide. Despite optimal treatment with modern antiepileptic drugs, about one third of patients will continue to have seizures, along with undesirable side effects. Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4). HCN channels have four isoforms (HCN1-4) and produce HCN-mediated currents (Ih) that exhibit pacemaker properties critical for regulating the hyperexcitable neuronal activity seen during seizures. This thesis explores the impact of both pharmacological and molecular HCN channel block on seizure susceptibility and neuronal excitability. Broad-spectrum HCN channel block using ivabradine significantly reduced the seizure susceptibility of wildtype and Scn1a Dravet mice in two proconvulsant assays. Testing isoform-selective HCN channel blockers, the HCN2/1-preferring channel blocker, MEL55A, increased seizure susceptibility. Whereas, the HCN1-preferring channel blocker, MEL57A, had no effect on seizure susceptibility. The HCN4-preferring channel blocker, EC18, significantly reduced seizure susceptibility in two proconvulsant assays in vivo while displaying a safe drug profile. Furthermore, the conditional knockout of HCN4 channels in adult mice was also sufficient to significantly reduce seizure susceptibility in proconvulsant tests with minimal behavioural effects. Interestingly, EC18 showed no effect on seizure susceptibility when administered intraperitoneally to the conditional HCN4 knockout mouse model indicating seizure protection is HCN4-dependant. Moreover, electrophysiological as well as multi-electrode array (MEA) recordings indicated a significant reduction in parameters relating to neuronal excitability after treatment with the HCN4-preferring channel blocker, EC18. Together these results indicate that HCN4 channels are important mediators of neuronal network excitability suggesting they are promising anti-seizure drug targets with minimal adverse effects.
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ItemEarly Mobilisation After Stroke: Barriers and Enablers for Effective Use of Population-Level Evidence to Inform Individualised Clinical Decision-Making( 2020)Early mobilisation, defined as sitting out of bed, standing or walking early after stroke, is an important constituent of acute stroke unit care. However, the multifaceted and complex nature of early mobilisation evidence and interventions, clinical practice guideline development and reporting, and the characteristics of stroke patients and their outcomes challenges individualised decision-making. The overall objective of this thesis was to investigate the barriers and enablers in the effective use of population-level evidence to inform individual patient-level clinical decision-making for early mobilisation post-stroke. The objective was achieved by conducting five studies: (1) a review of early mobilisation clinical practice guidelines as decision-support tools for individual patient-level decision-making; (2) a meta-analysis of individual participant data from EM trials, (3) an investigation of factors guiding early mobilisation decision-making by expert stroke clinicians, and investigation of how well (4) the utility-weighted modified Rankin scale, and (5) modified Rankin scale reflect post-stroke burden for an individual patient. (1) Based on the findings from the review of clinical practice guidelines, the decision-support requirements were met to a varying degree by early mobilisation clinical practice guidelines. Four key recommendations were formed for the future development of clinical practice guidelines. These included more granular descriptions of patient and stroke characteristics to allow tailoring of decisions to individual patients; clarity about when clinical flexibility is appropriate; a detailed description of the intervention dose, and physical assessment criteria including safety parameters. (2) The individual participant meta-analysis allowed the inclusion of individual patient-specific information and further strengthened earlier evidence from conventional meta-analyses that commencement of early mobilisation should only be considered after 24 hours post-stroke. It also reinforced the importance of adequate reporting of early mobilisation interventions to ensure the applicability of evidence to individual patients. (3) Interviews with expert stroke clinicians revealed that more than 80 percent of stroke experts considered stroke type and severity, medical stability to be the most important factors contributing to decision-making about early mobilisation. Inadequate staffing, equipment and low level of staff expertise were barriers for early mobilisation. (4) Based on the investigations of the utility-weighted modified Rankin scale, high variability in individual patient-centred utility values between and within mRS categories, over time post-stroke, and using different derivation methods was found. This variability is not adequately reflected in the utility-weighted modified Rankin scale. (5) Quality of life and activities of daily living domains demonstrated patient-specific patterns of post-stroke burden across the mRS and UW-mRS. From this research, gaps in the early mobilisation evidence base were identified that require future exploration of existing data and the development of new clinical trials to better support evidence-based clinical decision-making. Detailed areas of improvement for clinical practice guidelines as decision support tools were also identified to effectively translate population-level evidence to inform complex clinical decision-making at an individual patient-level. Finally, the identified multifaceted patterns of post-stroke burden across the utility-weighted modified Rankin scale and modified Rankin scale may facilitate appropriate assessment, articulation and interpretation of the outcomes for individual patient decision-making. The collective work has substantially contributed to systematically identifying the barriers and enablers in using population-level evidence to inform patient-level clinical decision-making in this challenging clinical context.
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ItemCharacterization of white matter asymmetries in the healthy human brain using Diffusion MRI fixel-based analysis( 2020)Magnetic resonance imaging (MRI) has revolutionized the way to investigate brain structural connectivity non-invasively. Diffusion MRI can be used to obtain local estimates of the white matter fibre orientations in the brain, which in turn can be used to study changes in the local fibre specific properties and/or in conjunction with fiber-tracking algorithm to reconstruct a representation of the white matter pathways in the brain. In recent years, the Diffusion Tensor model has played an important role in modelling the diffusion of water within white matter bundles. Diffusion tensor derived metrics such as fractional anisotropy (FA) have been used extensively for investigating white matter using approaches such as voxel-based analysis. One of the limitations of the diffusion tensor model is that it is not capable of appropriately modelling regions that have complex fibre architecture (such as crossing fibres). This makes tensor-derived measures unreliable measures to assess the white matter. Recent contributions toward the study of brain asymmetry have suggested asymmetry of brain anatomy and function are observed in the temporal, frontal, and parietal lobes. Several studies have used diffusion tensor model to study asymmetry in various regions of the human brain white matter. However, given the limitations of the tensor model, the nature of any underlying asymmetries remains uncertain. This research aims to provide to provide a more robust characterization of structural white matter asymmetries than those previously derived using the tensor model, by using quantitative measures derived from the spherical deconvolution model, and a whole-brain data-driven statistical inference framework such as Fixel-Based Analysis, that is both sensitive and specific to crossing fibres; we furthermore apply this approach to a state-of-the-art publicly available diffusion MRI dataset.
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ItemDeveloping peptidomimetic ligands for relaxin family peptide receptors( 2020)Relaxin family peptides that target G protein-coupled receptors (GPCRs), have important therapeutic applications (e.g., heart failure, fibrosis, cancer, and disorders related to psychiatry, drug addiction, eating, or colon motility). However, these family peptides have an insulin-like complex heterodimeric structure that is difficult to produce and modify to improve their pharmacokinetic properties (e.g., half-life). I have carried out structure-activity relationship (SAR) studies on these peptides leading to the generation of simplified agonists and/antagonists for the GPCRs, RXFP1, RXFP3, and RXFP4. These novel peptides are easier to prepare in larger yields and retain high affinity for their receptors. They are important research tools, and potential drug leads for the treatment of human diseases as mentioned above. Chapter 1 summarises the literature on the SAR studies of H2 relaxin, H3 relaxin and human INSL5 leading to the design and development of simplified agonist and antagonist. Chapter 2 describes all the materials and methods used in this study. Chapter 3 summarises the SAR studies on H2 relaxin. H2 relaxin is known to have strong anti-fibrotic, vasoprotective, angiogenic, and vasodilatory effects. The receptor for H2 relaxin, RXFP1, is a potential target for the treatment of heart failure, fibrosis and related disorders, including liver cirrhosis, and preeclampsia. Our laboratory has designed a B-chain-only analogue, B7-33, which was shown to be a potent RXFP1 agonist in cells endogenously expressing RXFP1 and in several animal models of fibrosis (mice vs rats). B7-33 is 27 residues long and has short circulation time in serum (t1/2= ~6 min). I have shown that B7-33 can be further truncated up to 4 residues, and it’s in vitro half-life in human serum can be increased from 6 minutes to 60 minutes. I also have developed a B7-33-based single-chain RXFP1 antagonist for the first time. These analogues are important research tools, and drug leads for the treatment of human diseases (e.g. fibrosis-related diseases, prostate, and other cancers). Chapter 4 summarises the SAR studies on the neuropeptide H3 relaxin. The receptor for the H3 relaxin hormone, RXFP3, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviours. This chapter has two parts. In the first part, I have developed four novel analogues based on two chains, and two disulfides bonded H3 relaxin analogue, also known as A2 analogue. I have introduced amide, alcohol, carbamate, and ester functionality at the C-terminus of the B-chain of A2 analogue. In terms of binding to RXFP3, the carboxylic acid remains to be the most suitable functionality. However, the cAMP response seems to be better with the C-terminal ester function. Such results highlight the possibility of generating drug candidates, as applied to H3 relaxin, to slow down the release or generating a long-acting analogue of H3 relaxin. In the second part, I have developed an alpha-helix stabilising chemical method. Using this method, I have produced a high yielding single-chain RXFP3 agonist and antagonist. The agonist peptide, H3B10-27-13/17alphaF, is 20-fold more stable in vitro in human serum compared with the control peptides (H3B10-27-13/17EA and H3B10-27-13/17FF). The novel RXFP3 antagonist, H3B10-22R-13/17alphaF, is only 14 amino acid long compared with the previously reported 23 residues antagonist. These analogues will facilitate the identification of physiological roles of RXFP3 and drug leads for the treatment of neurological disorders such as stress and anxiety. Chapter 5 summarises the SAR of insulin-like peptide 5 (INSL5), a gut hormone. Its receptor RXFP4 is a potential target for the treatment of anorexia, obesity, and colon motility disorders (e.g. constipation and diarrhoea). Our laboratory was the first to design and develop an RXFP4-specific agonist peptide known as analogue 13. However, there was no RXFP4-specific antagonist reported in the literature. The focus of this study was to utilise the non-specific RXFP3/RXFP4 antagonist, deltaR3/I5, as a template to design an RXFP4 specific antagonist rationally. Based on analogue deltaR3/I5, I have developed an analogue 17, which is RXFP4-selective. Analogue 17 is an ideal template for further development into a specific high-affinity RXFP4 antagonist as tool and drug leads. Chapter 6 summarises the findings in this study and provides future directions.
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ItemThe Role of MERTK in Central Inflammatory Demyelination( 2020)Multiple sclerosis (MS) is, at least in part, an autoimmune demyelinating disease of the central nervous system. It is the most common cause of neurological dysfunction in young adults. In addition to demyelination, autoimmune destruction in MS results in oligodendrocyte loss, local inflammation and neurodegeneration. Later in the disease course, a pattern of neurodegeneration may emerge without obvious evidence of adaptive immune activation. Current evidence implicates dysregulation of the innate immune system as a major contributor to the neurodegeneration of progressive MS. It is well established that innate immunity influences central nervous system damage and modulates myelin repair. The TAMs (TYRO3, AXL and MERTK) are a family of receptor tyrosine kinases expressed by discrete innate immune cell types, including macrophages, microglia and dendritic cells. They are involved the homeostatic regulation of adult, fully differentiated tissues that are subject to constant intrinsic and environmental challenge. The primary aim of this thesis was to provide additional insight into the biology of the MERTK receptor by examining its role in commonly employed mouse models of MS. In addition, I sought to identify whether serum levels of MERTK correlated with disease activity in MS patients experiencing relapse. I established that heterozygote deletion of Mertk in CD11+ve cells worsens the clinical severity of EAE in male mice, demonstrating for the first time that changes in the expression of a TAM receptor can alter the outcomes of a model of MS. Conversely, homozygous deletion did not result in EAE exacerbation. Heterozygote deletion of Mertk in CD11+ve cells does not alter the outcomes of cuprizone-induced demyelination, suggesting that CNS-resident CD11c+ve cells (microglia) are not implicated in the clinical exacerbation observed in EAE cohorts. In human subjects, MERTK expression by monocytes and dendritic cells does not correlate with periods of increased inflammatory activity in MS. MERTK expression by circulating dendritic cells is very limited. Taken together, the data in this thesis offer compelling evidence that MERTK is an important regulator of the outcomes of central inflammatory demyelination. They justify further research efforts in this area to better understand the mechanism of these disease states and to develop therapeutic targets for the treatment of MS.