Alpha 1-antitrypsin deficiency (ATD) is an autosomal recessive disorder characterized by mutations in SERPINA1. Since α1-antitrypsin (α1-AT) is the predominant serine peptidase inhibitor in extracellular fluids, decreased α1-AT secretion results in a loss-of-function phenotype manifested by peptidase-inhibitor imbalance, connective tissue matrix destruction, and susceptibility to chronic obstructive lung disease. In contrast, the accumulation of aggregation-prone alpha-1 antitrypsin-Z (ATZ) variant in liver cells leads to a toxic gain-of-function phenotype characterized by liver failure and carcinogenesis. Curiously, only ~10% of all ATZ homozygous individuals develop severe liver disease. This observation suggests that additional genetic disease modifiers and/or environmental conditions make an important contribution to disease severity and outcome. Our current understanding of these factors is incomplete and effective therapeutic options are very limited.
I report here the development of a C. elegans model of ATZ deficiency that recapitulates the ER transport defect associated with ATD. Furthermore, we identified key components of the disposal mechanism of ATZ in C. elegans, which parallels those in mammalian systems. Lastly, I developed a semi-automated high content genome-wide RNAi screen technology and used this method to identify <100 genes that modify the accumulation of ATZ. Many of these genes implicated in playing a role in the disposal of ATZ are novel and provide a source of potential ATZ genetic modifiers for future study.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08182011-100850 |
| Date | 25 August 2011 |
| Creators | Long, Olivia Sue |
| Contributors | Gary Silverman, Jeffrey Brodsky, Alfred Fisher, David Perlmutter, Michael Tsang |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08182011-100850/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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