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.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/42412 |
| Date | 15 November 2013 |
| Creators | Alayoubi, Abdulfatah |
| Contributors | Jeffrey, Medin |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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