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Title: Studies in the use of liposomes in the development of an animal model of Gaucher's disease
Author: Weereratne, Elaine Annmarie Hishani
Awarding Body: University of London
Current Institution: Royal Holloway, University of London
Date of Award: 1982
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Gaucher's disease is characterised by a malfunction of the enzyme glucocerebrosidase which hydrolyses the glycolipid glucocerebroside. Mammalian tissues contain at least two beta-glucosidases capable of releasing glucose from the synthetic substrate 4-methylumbelliferyl-beta-D-glucopyranoside (4-MUGlc). One of these enzymes, a membrane bound 'acid' form, also hydrolyses glucocerebroside and is deficient in patients with Gaucher's disease. The synthetic substrate is used to measure this latter enzyme in the routine diagnosis of Gaucher's disease. Diverse conditions have been used by different workers to assay this enzyme in various animal and tissue sources. An appropriate and reliable assay system to measure selectively the activity of the particulate β-glucosidase in crude mouse liver homogenate was developed. This revealed the possible existence of a hitherto unreported isoenzyme of glucocerebrosidase in mouse liver. Conduritol-B-epoxide (CBE) is a specific inhibitor of non-mammalian and mammalian beta-glucosidase. When injected into mice it produces some biochemical and certain pathological characteristics of Gaucher's disease which are very short-lived. Much of the injected dose is cleared rapidly via the kidneys. Liposomes are known to localise preferentially in the tissues of the reticuloendothelial system. It was established that administering liposomally-entrapped CBE greatly increased its localisation in the liver and spleenand reduced loss through the kidneys. Evaluation of the liposomal lipid composition which combined high entrapment with optimum stability revealed that liposomes composed of sphingomyelin/cholesterol (1:1, molar ratio) were the most suitable. The extent of inhibition as well as the rate of recovery of endogenous tissue beta-glucosidase was also investigated. Chronic administration of inhibitor entrapped within these liposomes produced the biochemical parameters of decreased enzyme activity and increased tissue glucocerebroside levels together with the tissue enlargement associated with Gaucher's disease. It was found that a toxicity effect of the liposomal lipid was responsible for the increased tissue size. Histological examination of the tissues revealed the presence of a widespread granulomatous inflammation incited by the administered lipid.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry