All ETDs from UAB

Advisory Committee Chair

Robert A Kesterson

Advisory Committee Members

James Collawn

Michelle Fanucchi

Steven Rowe

Bradley Yoder

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Rodents have been the model of choice for decades in biomedical research due to their relatively high physiological similarity to humans and amenability to genomic modification. While transgenic constructs were first used in mouse blastocysts in 1974 and the first mouse embryonic stem (ES) cell line created in 1981, the lack of reliable methods to produce ES cells or culture embryos from the rat led to the limitation of its use in spite of several advantages such as larger size and higher genetic homology with humans. Use of genetic modification has recently expanded due to the advent of tailored nucleases that induce site-specific double-stranded breaks and increase targeting efficiency by up to three orders of magnitude over conventional transgenics. Early nucleases such as zinc-fingers (ZFNs) and Transcription Activator-Like Effectors (TALENs) set the stage for Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) nucleases that exhibit ease of engineering and multiplexing along with low cellular toxicity and high targeting rates. The use of these reagents circumvents the need for ES cells, which when combined with refined surgical techniques and genome exchange methods, advance the creation of genetically modified rodents.

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