NIH Launches Knockout Mouse Project

The National Institutes of Health (NIH) has awarded a set of cooperative agreements, totaling up to $52 million over five years, to launch the Knockout Mouse Project.

The goal of this program is to build a comprehensive and publicly available resource of knockout mutations in the mouse genome.

The knockout mice produced from this resource will be useful for the study of human disease.

The NIH Knockout Mouse Project will work closely with other large-scale efforts to produce knockouts that are underway in Canada, called the North American Conditional Mouse Mutagenesis Project (NorCOMM), and in Europe, called the European Conditional Mouse Mutagenesis Program (EUCOMM).

The objective of all these programs is to create a mutation in each of the approximately 20,000 protein-coding genes in the mouse genome.

"Knockout mice are powerful tools for exploring the function of genes and creating animal models of human disease," said NIH Director Elias A. Zerhouni, M.D.

"By enabling more researchers to study these knockouts, this trans-NIH initiative will accelerate our efforts to translate basic research findings into new strategies for improving human health."

"It is exciting that so many components of NIH have joined together to support this project, and that the NIH Knockout Mouse Project will be working hand-in-hand with other international efforts. This is scientific teamwork at its best."

Knockout mice are lines of mice in which specific genes have been completely disrupted, or "knocked out."

Systematic disruption of each of the 20,000 genes in the mouse genome will allow researchers to determine the role of each gene in normal physiology and development.

Researchers will use knockout mice to develop better models of inherited human diseases such as cancer, heart disease, neurological disorders, diabetes and obesity.

Recent advances in recombinant DNA technologies, as well as completion of the mouse genome sequence, now make this project feasible.

NIH awarded five-year cooperative agreements totaling up to $47.2 million to two groups for the creation of the knockout mice lines.

Recipients of those awards are Regeneron Pharmaceuticals, Inc., in Tarrytown, N.Y., and a collaborative team from Children's Hospital Oakland Research Institute (CHORI) in Oakland, Calif.; the School of Veterinary Medicine, University of California, Davis (UC Davis); and the Wellcome Trust Sanger Institute in Hinxton, England.

In addition, NIH awarded another five-year cooperative agreement totaling $2.5 million to the Jackson Laboratory in Bar Harbor, Maine for the establishment of a NIH Knockout Mouse Project data coordination center.

Finally, NIH awarded cooperative agreements to the University of Pennsylvania in Philadelphia and to the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto to improve the efficiency of methods for creating knockout lines.

Those agreements total about $2.5 million and run for three and two years, respectively.

"Building a genome-wide library of knockouts will require the skills of researchers from many different disciplines," said James Battey, M.D., Ph.D., director of the National Institute on Deafness and Other Communication Disorders (NIDCD) and co-chair of the Trans-NIH Genomic Resources Working Group.

"We are confident that the multi-institution team we have pulled together will meet that challenge and deliver this much-needed resource into the hands of the worldwide research community."

To date, academic researchers around the world have created mouse knockouts of about 4,000 genes.

In addition, a random disruption strategy has been used by the International Gene Trap Consortium to mutate 8,000 mouse genes.

Due to some overlap between these efforts, about 15,000 genes remain to be knocked out in the mouse genome.

The NIH program, along with NorCOMM and EUCOMM, intend to closely coordinate their efforts in order to avoid redundancy and maximize the efficiency of generating knockouts for all genes in the mouse genome.

Furthermore, the U.S., Canadian and European groups are committed to making their data and resources rapidly and openly available to researchers around the world.

"The international projects will exchange information and coordinate their efforts in much the same way that teams from many nations collaborated on the International Human Genome Project," said Colin Fletcher, Ph.D., a program director at the National Human Genome Research Institute (NHGRI), which will oversee administration of three of the five cooperative agreements that form the core of the Knockout Mouse Project.

"Development of ES cell lines that can be used to make mutants in the C57BL/6 strain will be an important step forward in capitalizing on the vast amount of information obtained from years of research already done in this mouse strain," said NIDA Director Nora D. Volkow, M.D.