Genetics team to create hundreds of new knockout rats to study human disease

Feb. 13, 2014 College News - The Medical College of Wisconsin (MCW) has received a five-year, $8.7 million grant from the National Institutes of Health’s National Heart, Lung and Blood Institute to create 200 gene-targeted rat models to study the genetics of human disease.

Howard Jacob, PhD, Warren P. Knowles Professor in Human and Molecular Genetics and Director of the Human and Molecular Genetics Center at MCW, is the primary investigator of the grant.

Rats are physiologically more similar to humans than mice for many traits, and breed rapidly, which makes them ideal subjects for modeling human diseases. Approximately 90 percent of the rat’s 25,000-30,000 estimated genes are analogous to those in humans.

In this project, researchers will use gene editing using transcription activator-like effector nuclease (TALEN) technology to “knock out,” “knock in,” or otherwise edit, specific nucleotides in genes in rats to understand their function. Gene editing technologies induce breaks at specific sites in an organism’s DNA; the resulting repair results in site-specific changes in the DNA.  When a repair template is provided, the new sequence is inserted into the double strand break. The specificity and efficiency of the gene editing is revolutionizing our ability to make genetically modified animals.

Dr. Jacob’s team was the first to use gene editing to create knockout rats, and has generated more than 100 strains in the last two years that have served as models for disease processes related to hypertension, heart disease, kidney failure, and cancer – the most common and costly human diseases.  The Medical College of Wisconsin is also home to the Rat Genome Database, a collaborative effort between leading international research institutions involved in rat genetic and genomic research that allows researchers to access the most current, complete set of rat genomic and genetic data available, as well as the most innovative tools for analyzing the data.

The new strains will accelerate scientific discovery, and increase the field’s understanding of the mechanisms involved in complex diseases.  The genes to be modified will be selected from applications to the Gene Editing Rat Resource Center.

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