Knockout Mouse Project: Genome-wide, Public Resource Will Provide New Mouse Mode

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Knockout Mouse Project: Genome-wide, Public Resource Will Provide New

Mouse Models For Understanding Human Disease

http://www.medicalnewstoday.com/medicalnews.php?newsid=51467

The National Institutes of Health (NIH) today 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 extremely 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. 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, " said NIH Director Elias A.

Zerhouni, M.D. " 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.

Even more importantly, 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 today 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, (UC

); and the Wellcome Trust Sanger Institute in Hinxton, England.

In addition, NIH awarded another five-year cooperative agreement

totaling $2.5 million to the Laboratory in Bar Harbor, Maine

for the establishment of an NIH Knockout Mouse Project data

coordination center. Finally, NIH awarded cooperative agreements to

the University of Pennsylvania in Philadelphia and to the

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. 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, " said 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.

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.

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 ;

and Allan Bradley, Ph.D. FRS, and Skarnes, Ph.D., at the

Wellcome Trust Sanger Institute, plans to systematically create mouse

embryonic stem (ES) cell lines in which 5,000 genes have been knocked

out by gene targeting. The VelociGene division of Regeneron, led by

Valenzuela, Ph.D. and 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.

Other researchers will be able to obtain the ES cells and the

vectors, which can be used to swiftly and efficiently to make live

lines of knockout mice for use in biomedical studies. During the

initial phase of the project, the ES cell lines and vectors used to

mutate the genes will be available from the grantees who produced

them. In addition, NIH is preparing to issue a solicitation for a

program to implement a Knockout Mouse Project repository, which will

be funded in the next year and through which all these materials will

be available to the entire scientific community.

Another crucial component of the effort will be the collection and

coordination of data. Under the leadership of Ringwald, Ph.D.,

the 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.

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

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.

" 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.

While today's awards mark the official launch of the Knockout Mouse

Project, NIH has been laying the foundation for several years. In the

fall of 2003, NIH co-sponsored an international meeting that

concluded that the time was right for a coordinated effort to produce

knockouts in every mouse gene, and a commentary calling for such a

project was published in the September 2004 issue of Nature Genetics,

http://www.genome.gov/Pages/About/RecentArticles/AustinKnockoutMouseCo

mmentary.pdf.

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 , 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:

http://www.nih.gov/science/models/mouse/deltagenlexicon/list.html.

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

and the University of Missouri/Harlan in Columbia, both

supported by the National Center for Research Resources (NCRR). 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: http://www.mmrrc.org/

The 19 NIH institutes, centers and offices contributing to the

Knockout Mouse Project are: NCRR, 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, NIDCD, 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.