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dc.contributor.advisorHaydar, Tariken_US
dc.contributor.authorO'Neill, Sharon M.en_US
dc.date.accessioned2018-07-17T13:46:34Z
dc.date.issued2018
dc.identifier.urihttps://hdl.handle.net/2144/29954
dc.description.abstractMultiple sclerosis (MS) is a chronic central nervous system disease featuring exacerbations of inflammation and demyelination that cause progressively debilitating clinical effects over time. Current treatments for multiple sclerosis are limited in their ability to impact overall disease progression. Research aimed at generation of novel potential therapeutics for MS is needed. Recently, kallikrein 6 (KLK6), a member of the kallikrein (KLK) family of secreted serine proteases, was found to be elevated in the cerebrospinal fluid and brain of MS patients. The fifteen known tissue-based KLKs cleave proteins through a similar mechanism, but have different binding pocket specificity, diverse localization in human tissues, and multiple biological functions. KLKs have been linked to normal human physiology (e.g. KLK4, enamel formation) and disease (e.g. KLK3, prostate cancer). KLK6 is one of the highest expressed serine proteases in the healthy human brain and is expressed predominately in mature oligodendrocytes in both human and mouse brain. The role of KLK6 in oligodendrocyte maturation, myelination, and disease is not fully understood. To evaluate the role of KLK6 in oligodendrocyte maturation, I used a pluripotent in vitro primary cell system to assess the impact of exogenous KLK6 and modulators of the KLK6 pathway on oligodendrocyte maturation. I demonstrate that signaling through KLK6 decreases the number of mature oligodendrocytes in culture, whereas blockade of KLK6 signaling increases the number of mature oligodendrocytes in culture in the presence of triiodothyronine higher than either agent alone. This work suggests that KLK6 modulation impacts oligodendrocyte maturation. To understand the potential impact of KLK6 pathway inhibition on remyelination, I used the toxin cuprizone to induce demyelination in mice. I found that animals treated with a KLK6 inhibitor had increased myelin staining in the corpus callosum compared to vehicle-treated. This work suggests that KLK6 modulates oligodendrocyte maturation and myelination and may be relevant for improving myelin-related therapeutic outcomes, particularly in multiple sclerosis.en_US
dc.language.isoen_US
dc.subjectNeurosciencesen_US
dc.subjectKLK6en_US
dc.subjectKallikrein 6en_US
dc.subjectMultiple sclerosisen_US
dc.subjectOligodendrocyte maturationen_US
dc.subjectRemyelinationen_US
dc.titleElucidating the role of serine protease kallikrein 6 in oligodendrocyte maturation & myelinationen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2018-06-12T22:12:49Z
dc.description.embargo2019-06-12T00:00:00Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineAnatomy & Neurobiologyen_US
etd.degree.grantorBoston Universityen_US


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