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DC Field | Value | Language |
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dc.contributor.advisor | Igdoura, Suleiman | - |
dc.contributor.author | Johnson, Matthew | - |
dc.date.accessioned | 2018-05-29T18:17:41Z | - |
dc.date.available | 2018-05-29T18:17:41Z | - |
dc.date.issued | 2002-12 | - |
dc.identifier.uri | http://hdl.handle.net/11375/22984 | - |
dc.description.abstract | Tay-Sachs disease and its related disorders (GM2 gangliosidoses) are neurodegenerative diseases caused by the excessive accumulation of ganglioside GM2, an otherwise non-toxic plasma membrane component, in the lysosomes of cells of the central nervous system. The accumulation of ganglioside GM2 is the result of a defect in the gene encoding the α-subunit of β-hexosaminidase A (Hex A), an acid hydrolase responsible for the metabolism of gangloside GM2 in the lysosome. Though a debilitating disease in humans, Tay-Sachs model mice (𝘏𝘦𝘹𝘢-/-) escape symptoms by the action of lysosomal sialidase, which is expressed in mice at levels sufficient to metabolize ganglioside GM2 and effectively "bypass" Hex A deficiency. In an attempt to understand why a lysosomal sialidase-mediated bypass of Hex A deficiency is not observed in humans, we cloned ~ 2.9 kb of the human lysosomal sialdiase promoter and began characterization of the regulatory machinery that determines its activity. The transcription factor CDP (CCAAT -Displacement Protein) and truncations thereof were found to have a clear and consistent effect on promoter activity 𝘪𝘯 𝘷𝘪𝘵𝘳𝘰, with the truncation CDP⁸³¹⁻¹⁵⁰⁵ resulting in a near 50-fold increase in activity. Adenovirus-mediated gene transfer of CDP⁸³¹⁻¹⁵⁰⁵ into CRB/TSD cells, a human Tay-Sachs neuroglia cell line, resulted in elevated lysosomal sialidase activity and a decrease in ganglioside GM2 stores. These results suggest that the regulatory machinery responsible for lysosomal sialidase expression may be manipulated in such a way as to "activate" a sialidase-mediated bypass of Hex A deficiency in human Tay-Sachs cells. Thus, induction of lysosomal sialidase may have a potential therapeutic benefit in human Tay-Sachs disease and other Hex A-deficient GM2 gangliosidoses. | en_US |
dc.language.iso | en | en_US |
dc.subject | human | en_US |
dc.subject | lysosome | en_US |
dc.subject | sialidase | en_US |
dc.subject | tay-sachs | en_US |
dc.subject | therapy | en_US |
dc.title | The Human Lysosomal Sialidase Promoter: Characterization and Stimulation as a Potential Therapy for Tay-Sachs Disease | en_US |
dc.title.alternative | The Human Lysosomal Sialidase Promoter | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Biology | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Master of Science (MS) | en_US |
Appears in Collections: | Digitized Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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johnson_matthew_w_2002Dec_masters.pdf | 10.06 MB | Adobe PDF | View/Open |
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