Long, Olivia Sue
(2011)
Genetic Modifiers that Affect the Accumulation of the Mutant Protein Alpha-1 Antitrypsin-Z.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
25 August 2011 |
| Date Type: |
Completion |
| Defense Date: |
11 August 2011 |
| Approval Date: |
25 August 2011 |
| Submission Date: |
18 August 2011 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Biochemistry and Molecular Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Alpha-1 Antitrypsin; Alpha-1 Antitrypsin Deficiency; C. elegans; Genome-wide RNAi screen; RNAi |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08182011-100850/, etd-08182011-100850 |
| Date Deposited: |
10 Nov 2011 20:00 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9182 |
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