Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754402
Title: Elucidating the functions of fibroblast growth factor 9 in multiple sclerosis
Author: McElroy, Daniel
ISNI:       0000 0004 7427 4397
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2018
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Abstract:
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. In around 85% of cases, the disease progresses through two distinct stages: relapsing-remitting MS (RRMS) is driven by repeated bouts of demyelination caused by autoimmune inflammation; and progressive MS, in which inflammation gives way to neurodegenerative processes that lead to axonal loss and the steady accumulation of disability. There is no cure for MS and the majority of disease-slowing treatments target the immune response in RRMS. These interventions are ineffective in progressive MS and other treatment options are extremely limited. Understanding the mechanisms underlying neurodegeneration in MS is critically important to developing therapeutics for progressive disease. Fibroblast growth factor 9 (FGF9) has recently been implicated in the pathogenesis of MS. FGF9 inhibits myelination and promotes the production of inflammatory chemokines. This led to the hypothesis that FGF9 is involved in remyelination failure and may promote neurodegeneration via tissue remodelling and inflammatory pathways. FGF signaling is complex and the findings in MS raised many questions: what cells respond to FGF9 in MS? Why is FGF9 expression induced in the first place? Can FGF9 cause demyelination as well as inhibit myelination? This thesis has focused on the roles of FGF9 in MS and tried to answer these questions. Through in vitro models, astrocytes, oligodendrocytes, and macrophages were shown to express feedback inhibitors of FGF signaling when treated with FGF9. Astrocytes produced FGF9 in response to hypoxic stress, macrophages expressed FGF9 when polarized towards an anti-inflammatory phenotype, suggesting hypoxia, and repair processes may drive FGF9 expression in the CNS. FGF9 did not cause demyelination in vitro but over-expression in vivo induced severe demyelination over the course of several months. Oligodendrocytes exposed to FGF9 failed to differentiate properly when the factor was removed which led to aberrant myelination. Long-term treatment with FGF9 induced axonal pathology, potentially via deficits in axon-transport. Over-expression of FGF9 in rat cortex also produced an axonal pathology, which suggests chronic exposure is detrimental to neurons. Together, these findings indicate that increased levels of FGF9 are detrimental to myelination and neurons in the CNS. Demyelination, and axonal pathology are hallmarks of MS and these studies provide evidence that FGF9 can mediate these processes in in vitro and in vivo models.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.754402  DOI: Not available
Keywords: RC Internal medicine
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