Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607031
Title: The role of Secretory Leukocyte Protease Inhibitor (SLPI) in progranulin regulation and neurodegeneration
Author: Toulson, Gregory
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Abstract:
Frontotemporal lobar degeneration (FTLD) is an early onset neurodegenerative disorder which selectively destroys frontal and temporal cortical neurones. The resulting damage leads to a range of language and behavioural deficits, however, episodic memory is generally maintained. Around 10% of FTLD cases are caused by progranulin gene mutations that lead to haploinsufficiency and reduced expression of progranulin. Secretory leukocyte protease inhibitor (SLPI) has been shown to have a key protective effect over progranulin, inhibiting enzymatic cleavage by neutrophil elastase. Previous work demonstrating this role of SLPI is largely from in vitro studies and scenarios with above-physiological SLPI concentrations. To ascertain a role for endogenous SLPI in the regulation of progranulin a murine SLPI knockout model was used and tonic progranulin measurements taken. No change in circulating progranulin levels were seen in SLPI null mice (at 6, 12 or 20 months of age) when compared to non-transgenic controls, though significant differences were observed between male and female SLPI null animals. Similarly, tissue (brain and lung) levels of progranulin were comparable between wild-type and SLPI null mice, despite the presence of active neutrophil elastase. Behavioural analysis of SLPI null mice revealed no major phenotype when compared to wild-type, over a range of behavioural tests. However primary neuronal cultures taken from SLPI null mice did display an elevated progranulin response to bacterial lipopolysaccharide (LPS). These data suggest that, although SLPI may play a role in progranulin regulation during an inflammatory event, it is unlikely to play a major role in progranulin regulation under basal conditions, as reported previously. Therefore under disease conditions regulation of extracellular progranulin is likely through other modulatory factors that have yet to be described.
Supervisor: Allan, Stuart; Pickering-Brown, Stuart Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.607031  DOI: Not available
Keywords: SLPI, Progranulin, FTLD, Mouse models, Behavioral testing, Dementia.
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