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Environmental Factor, October 2012

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Mouse studies may help unravel human illnesses

By Robin Arnette

Monica Justice, Ph.D.

Justice said that 70 percent of lethal homozygous mutations produce related phenotypes in adults as heterozygotes. She said, “We think these are the ones that are more likely to model human diseases since many human diseases are really semi-dominant in origin, and not recessive.” (Photo courtesy of Steve McCaw)

Can studying mice help scientists better understand human diseases? According to this month’s NIEHS Distinguished Lecturer, mouse geneticist Monica Justice, Ph.D., the answer is a resounding yes.

Justice is a professor in the Department of Molecular and Human Genetics and director of the Mouse Embryonic Stem (ES) Cell Core Facility at Baylor College of Medicine in Houston, Texas. She came to NIEHS Sept. 13 to talk about the second phase of the Knockout Mouse Project (KOMP) called KOMP2. KOMP2 is funded by the National Institutes of Health and is an initiative for three centers at Baylor College of Medicine, the University of California-Davis, and The Jackson Laboratory. The project focuses on the phenotypic analysis of mice, or the study of the physical makeup of mice as determined by genetic and environmental influences. She hopes the new program will reveal the function of genes in the mammalian genome.

Justice contributes to KOMP2 by heading the BaSH consortium, a collaboration of Baylor College of Medicine, the Sanger Institute, and the MRC Harwell Mouse Genome Centre, United Kingdom. She said the idea for KOMP2 originally came from a 2003 gathering of mouse geneticists at Cold Spring Harbor who wanted to knockout all of the genes in the mouse genome to better understand human sequencing studies. The work has now grown to become part of a larger international effort called the International Mouse Phenotyping Consortium (IMPC), with KOMP2 serving as one of the founding members.

“We are developing standard phenotyping platforms, as well as common quality control standards for the program,” Justice said of KOMP2’s contribution to IMPC. “Our goal is to produce a global resource of knockout mice and an entire database of gene function for all of the genes in this program.”

KOMP2 finds previously unknown gene functions

According to Justice, KOMP2 has 14,000 conditional-ready ES cells, or ES cells for 14,000 genes, which will be transmitted into mice that will undergo phenotyping. The phenotyping pipeline tests neurological behavior, metabolism, cardiovascular, pulmonary, reproduction, sensory, muscular-skeletal, immune, and general overall health.

One of the first genes KOMP2 examined is called Akt1s1. Justice said that it links energy and nutrients to cell growth and metabolism and is known to function in human cancer and type 2 diabetes. After knocking out Akt1s1, they noticed that the homozygotes died prior to embryonic day 12.5 with complete cardiovascular failure, suggesting that the gene’s primary function may involve the circulatory system.

The researchers then took the heterozygotes through the phenotyping pipeline, and tests revealed these mice had abnormal glucose clearance, regressed vasculature in the eye, and an increased pause and breath frequency as compared to wild-type mice. Justice said that the KOMP2 phenotyping pipeline is invaluable in characterizing genes because the results identify excellent human disease models to study.

NIEHS Deputy Scientific Director William Schrader, Ph.D., invited Justice and served as host for the seminar because the Institute is interested in carrying out its own neurobiological testing of mice. He knew that NIEHS would benefit from her expertise.

“Dr. Justice not only provided NIEHS with an excellent scientific seminar, but she also shared her considerable experience in mouse phenotyping with [Scientific Director] Dr. Zeldin and the Division of Intramural Research investigators who require this capability,” Schrader said.

Christopher Campos, Ph.D.

Christopher Campos, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the Laboratory of Toxicology and Pharmacology. He studies how therapeutic agents cross the blood-brain barrier in rodents and was interested in several of the phenotyping tests Justice discussed. (Photo courtesy of Steve McCaw)

William Schrader, Ph.D.

As head of the NIEHS Mouse Information Management System, Schrader said phenotyping data would greatly improve the current system. (Photo courtesy of Steve McCaw)

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