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Genetic Modifiers that Affect the Accumulation of the Mutant Protein Alpha-1 Antitrypsin-Z

Long, Olivia Sue (2011) Genetic Modifiers that Affect the Accumulation of the Mutant Protein Alpha-1 Antitrypsin-Z. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Long, Olivia
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee CoChairSilverman,
Committee CoChairTsang, MichaelTsang@pitt.eduTSANG
Committee MemberFisher, AlfredFisherA@dom.pitt.eduAFISHER
Committee MemberPerlmutter, Daviddhp6@pitt.eduDHP6
Committee MemberBrodsky, JeffreyJBrodsky@imap.pitt.eduJBRODSKY
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:, etd-08182011-100850
Date Deposited: 10 Nov 2011 20:00
Last Modified: 19 Dec 2016 14:37


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