Trans-NIH Mouse Initiative

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NIH Knockout Mouse Project (KOMP)
* NIH Knockout Mouse Project (KOMP)


What is KOMP?

The Knockout Mouse Project is a trans-NIH initiative that aims to generate a comprehensive and public resource comprised of mouse embryonic stem (ES) cells containing a null mutation in every gene in the mouse genome. By capitalizing on efficiencies of scale and a centralized production effort, the project intends to make this catalog of mutants available in mouse strain C57BL/6 for two reasons: it is the most widely used strain and it is the strain for which complete genome sequence has been made available. This concept for the KOMP was developed at an international workshop held at the Banbury Center in the autumn of 2003 (and published in Austin, et al., Nature Genetics, September 2004). The meeting attendees agreed that such a comprehensive resource of null mutants would greatly benefit the biomedical research community and enhance our understanding of human disease. Acting on the outcome of this meeting, the National Human Genome Research Institute (NHGRI) organized a working group of NIH Institute and Center representatives to plan the role that NIH should play in implementing this goal. In developing the NIH KOMP plan, this working group evaluated the current state of the field and solicited recommendations from members of mouse research community during a second workshop in March, 2005. (see http://www.genome.gov/15014549 for an executive summary).

In brief, the NIH KOMP initiative aims to: 1) use gene targeting to make the resource of null alleles, marked with a high utility reporter, preferably in C57BL/6; 2) support a repository to house the products of this resource as well as an additional ‘repatriation' effort to bring into repositories 1000 of the existing high priority mouse knockouts not already stored in a public repository; 3) develop improved C57BL/6 ES cells that show robust germline transmission, so that they may be used in a high throughput pipeline in generating this resource; and 4) implement a data coordination center which will make the status and relevant data of the production effort available to the research community.

Towards those ends, 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. Under its cooperative agreement, the team led by Pieter deJong, Ph.D., CHORI, along with K. C. Kent Lloyd, D.V.M., Ph.D., UC Davis; and Allan Bradley, Ph.D. FRS, and William Skarnes, Ph.D., at the Wellcome Trust Sanger Institute, plans to systematically create mouse ES cell lines in which 5,000 genes have been knocked out by gene targeting. The VelociGene division of Regeneron, led by David Valenzuela, Ph.D. and George D. Yancopoulos, M.D., Ph.D., will take aim at a different set of 3,500 genes. Both groups will utilize information from the finished mouse genome sequence to design targeting vectors, which will be built by large-scale, automated technologies. The combined collection of mouse ES cells with knockouts in 8,500 genes will be useful for producing knockout mice.

In addition, NIH awarded another five-year cooperative agreement totaling $2.5 million to the Jackson Laboratory in Bar Harbor, Maine. Under the leadership of Martin Ringwald, Ph.D., the Jackson Laboratory will set up a Data Coordination Center for the Knockout Mouse Project. The center will collect information that will allow the research community to track the scheduling and progress of knockout production. The center will also serve as a central information resource for all publicly available knockout mutants and will integrate with other databases that contain mouse DNA sequence, additional information on mouse genetics and information on the physical and biochemical characteristics of the knockout mice. The URL for this website is www.knockoutmouse.org .

The NIH has also provided $4.8 million to establish and support a repository for the Knockout Mouse Project. This award is the final component of the trans-NIH initiative to increase the availability of genetically altered mice and related materials. The University of California, Davis (UC Davis) and Children's Hospital Oakland Research Institute (CHORI) in Oakland, Calif., will collaborate to preserve, protect, and make available about 8,500 types of knockout mice and related products available to the research community. More information about the KOMP resources is available at www.komp.org. To request information or products, researchers can call 1-888-KOMP-MICE or e-mail service@komp.org.

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. Under two cooperative agreements administered by the National Institute on Drug Abuse (NIDA), Klaus Kaestner, Ph.D., and his colleagues at the University of Pennsylvania will focus on developing methods to create ES cell lines suitable for high-throughput gene targeting or trapping in C57BL/6, the strain of mouse used most widely by the scientific community. They will be joined in this effort by Andras Nagy, Ph.D., and his colleagues at the Samuel Lunenfeld Research Institute. In addition, Regeneron will receive funds to optimize its existing ES cell line for the C57BL/6 strain and its proprietary growth medium, both of which will be supplied to the CHORI-led team for use in the Knockout Mouse Project.

The 19 NIH institutes, centers and offices contributing to the Knockout Mouse Project are: National Center for Research Resources, National Eye Institute, NHGRI, National Heart, Lung and Blood Institute, National Institute on Aging, National Institute of Alcohol Abuse and Alcoholism, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Child Health and Human Development, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, NIDA, National Institute of Environmental Health Sciences, National Institute of General Medical Sciences, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Diabetes and Digestive and Kidney Disease, National Cancer Institute, and the Office of AIDS Research.

While these awards mark the official launch of the Knockout Mouse Project, NIH has been laying the foundation for several years. In October 2005, NIH and the U.K.'s Wellcome Trust took the first concrete step by awarding contracts that gave academic researchers access to a set of well-characterized knockout mouse lines created by Deltagen, Inc. of San Carlos, Calif., and Lexicon Genetics, Inc. of The Woodlands, Texas. NIH has expended about $11 million to acquire about 250 lines of these mice in the first year of the three-year contracts. Researchers can obtain information on what knockout mouse lines are available from this procurement and how to order them at: Deltagen and Lexicon Knockout Mice and Phenotypic Data.

In June, NIH moved another step closer to its goal of a genome-wide library of knockout mice with the award of $800,000 to two public mouse repositories for the acquisition of existing knockout mouse lines that are not yet widely accessible to researchers. The award recipients were the Mutant Mouse Regional Resource Centers at UC Davis and the University of Missouri/Harlan in Columbia, both supported by the National Center for Research Resources. NIH anticipates that more than 350 existing mouse lines will be deposited and made available to the research community over the next two years as a result of this effort. Researchers can obtain information on what knockout mouse lines are available from this effort and how to order them at: Mutant Mouse Regional Resource Centers.

Links to the funded KOMP RFAs (issued September 2005/2006)

1. HG-05-007: The Completion of a Comprehensive Mouse Knockout Resource

2. DA-06-009: Development and Improvement of Inbred ES Cell Lines for Use in Generation of Mouse Mutants

3. HG-05-008: A Data Coordination Center for the Knockout Mouse Project (KOMP)

4. RR-06-005: Knockout Mouse Project (KOMP) Repository