"February, 2003" / Addendum inside front cover. / Bibliograpy: leaves 200-219. / xiv, 219, xiv leaves : ill. (some col.), plates (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2003

Thesis (M.A.)--York University, 2005. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 103-116). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url%5Fver=Z39.88-2004&res%5Fdat=xri:pqdiss &rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR11798

Thesis (Ph.D.) -- McMaster University, 2002. / Includes bibliographical references (leaves 189-243). Also available via World Wide Web.

Thesis (M.S.)--Rutgers University, 2009. / "Graduate Program in Microbiology and Molecular Genetics." Includes bibliographical references (p. 63-71).

Farber disease is a fatal inherited disorder of lipid metabolism. It is characterized by a deficiency of the lysosomal enzyme acid ceramidase (AC), resulting in the buildup of the bio-effector molecule ceramide. A previous attempt to generate a Farber mouse model by Asah1 knockout was unsuccessful owing to embryonic lethality in homozygous embryos. Here, we successfully generated viable homozygotes that developed Farber disease by introducing a single-nucleotide human patient mutation into a conserved region of murine Asah1 (P361R). Indeed, homozygotes manifested Farber disease symptoms and died within 7-13 weeks. Furthermore, treatment of neonatal pups with intravenous injections of AC lentiviral vectors (LVs) yielded homozygotes with intermediate Farber phenotypes highlighted by reduced symptoms and increased longevity. Therefore, this first model of Farber disease can facilitate the advancement of experimental therapies and offer mechanistic insights into the integral roles of acid ceramidase, ceramide, and related sphingolipids in cell signaling, growth, and oncogenesis.

Farber disease is a fatal inherited disorder of lipid metabolism. It is characterized by a deficiency of the lysosomal enzyme acid ceramidase (AC), resulting in the buildup of the bio-effector molecule ceramide. A previous attempt to generate a Farber mouse model by Asah1 knockout was unsuccessful owing to embryonic lethality in homozygous embryos. Here, we successfully generated viable homozygotes that developed Farber disease by introducing a single-nucleotide human patient mutation into a conserved region of murine Asah1 (P361R). Indeed, homozygotes manifested Farber disease symptoms and died within 7-13 weeks. Furthermore, treatment of neonatal pups with intravenous injections of AC lentiviral vectors (LVs) yielded homozygotes with intermediate Farber phenotypes highlighted by reduced symptoms and increased longevity. Therefore, this first model of Farber disease can facilitate the advancement of experimental therapies and offer mechanistic insights into the integral roles of acid ceramidase, ceramide, and related sphingolipids in cell signaling, growth, and oncogenesis.

Dissertation (Ph.D.)--Auburn University, 2005. / Abstract. Vita. Includes bibliographic references.

Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, Discipline of Paediatrics, 2007. / "June 2007" Includes Addenda attached to back page. Bibliography: leaves 215-274. Also available in print form.

Pour valider une suite de biomarqueurs cellulaires en milieu dulçaquicole, nous avons étudié la structure des systèmes lysosomal et peroxysomal et les variations de contenus en lipofuscines et lipides neutres insaturés dans les tissus digestifs de plusieurs invertébrés, à travers une approche couplant histochimie et analyse d’images. Les expérimentations in situ et bioessais à plus ou moins long terme ont montré la pertinence des réponses cellulaires étudiées pour la mise en évidence de gradients de contamination. Les profils de réponse les plus communs chez les mollusques incluent un gonflement lysosomal, des déplétions de lipides neutres insaturés, une accumulation de lipofuscines et/ou un système peroxysomal plus volumineux. Ces réponses cellulaires précoces peuvent être associées, au niveau individuel, à une désynchronisation de la reproduction entre individus ou à une diminution de l’indice de condition. L’étude mensuelle à long terme (2 ans) a souligné l’absence de niveaux de base saisonniers de ces biomarqueurs et l’influence importante de la disponibilité trophique sur les contenus tissulaires en lipides neutres. Une mise en dépuration de 15 jours du bivalve, Dreissena polymorpha, sur son site d’origine, n’a pas montré de réversibilité du profil des réponses cellulaires à un gradient de contamination in situ, mais elle a tout de même de limité la déplétion des lipides neutres. Les réponses cellulaires les plus précoces et discriminatives sont le gonflement lysosomal et la déplétion en lipides neutres. Une comparaison d’outils d’analyse intégrative a montré le pouvoir discriminatif accru de la suite de biomarqueur entière, par rapport aux réponses individuelles / To validate a cellular biomarker suite, we studied the lysosomal and peroxisomal structures as well as the variations of the lipofuscin and unsaturated neutral lipid contents in the digestive tissues of several freshwater invertebrates, by using histochemistry coupled to image analysis. Cellular responses, studied through field and laboratory experiments proved relevant to highlight contamination gradients. The most frequent response profiles in molluscs were lysosomal enlargement, unsaturated neutral lipid depletions, lipofuscin accumulations and a more voluminous peroxisomal system. These early cellular responses may be associated, at the individual level, to a desynchronisation of the reproduction or to decreased condition index. A long-term monthly experiment showed no seasonal baseline levels of these biomarkers and underlined the important influence of trophic factors on the unsaturated neutral lipid contents. A 15-day depuration period of the bivalve, Dreissean polymorpha, at the site of origin after an exposure to a comparison of integrative analysis tools proved that the whole biomarker suite discriminates better between sites than individual responses

BACKGROUND: The lysosomal storage disorder, Niemann Pick type C1 (NPC1), presents a variable phenotype including neurovisceral and neurological symptoms. 2-Hydroxypropyl-ss-cyclodextrin (HPssCD)-based therapies are presently the most promising route of intervention. While severe cerebellar dysfunction remains the main disabling feature of NPC1, sensory functions including auditory and olfactory ones are also affected. Morphological and functional anomalies of Npc1 (-/-) mouse retina have also been observed, although the functional integrity of the visual pathway from retina to visual cortex is still unsettled. We have addressed this issue by characterizing the visual evoked potential (VEP) response of Npc1 (-/-) mice and determining if/how HPssCD administration influences the VEPs of both Npc1 (-/-) and Npc1 (+/+) mice. METHODS: VEP elicited by a brief visual stimulus were recorded from the scalp overlying the visual cortex of adult (PN, postnatal days 60, 75, 85 and 100) Npc1 (+/+) and Npc1 (-/-) mice that had received repeated injections of either HPssCD or plain vehicle. The first injection was given at PN4 and was followed by a second one at PN7 and thereafter by weekly injections up to PN49. Cholesterol accumulation and myelin loss were finally assessed by filipin staining and myelin basic protein immunohistochemistry, respectively. RESULTS AND DISCUSSION: We have found that the transmission of visual signals from retina to visual cortex is negatively influenced by the loss of Npc1 function. In fact, the VEP response of Npc1 (-/-) mice displayed a highly significant increase in the latency compared to that of Npc1 (+/+) mice. HPssCD administration fully rescued this defect and counteracted the cholesterol accumulation in retinal ganglion cells and dorsal lateral geniculate nucleus neurons, as well as the myelin loss in optic nerve fibers and axons projecting to the visual cortex observed in of Npc1 (-/-) mice. By contrast, HPssCD administration had no effect on the VEP response of Npc1 (+/+) mice, further strengthening the treatment efficacy. CONCLUSIONS: This study pinpoints the analysis of VEP response as a potentially accurate and non-invasive approach to assess neural activity and visual information processing in NPC1 patients, as well as for monitoring the progression of the disease and assessing the efficacy of potential therapies.