Baylor College of Medicine leads one of three groups that has received a total of $110 million from a trans-National Institutes of Health project over the next five years to build a better mouse model – in fact a library of knockout mice that will enable scientists to identify the function of important protein-coding genes in the mammalian genome and to better understand disease.
Phase 2 of the Knockout Mouse Phenotyping Project, in cooperation with the International Knockout Mouse Phenotyping Consortium, will create 5,000 strains of knockout mice and determine their physical characteristics. Knockout mice are bred to lack a specific gene – either in all their tissues or only in specific tissues or at a specific time. In its first phase, the project started the process of creating mouse embryonic stem cell lines for each of the approximately 21,000 protein-coding genes in the mouse genome.
Reaching out to the world
"Baylor's commitment to creating a mouse infrastructure in prior years contributed to our ability to obtain this grant," said Dr. Monica Justice, professor of molecular and human genetics at BCM and principal investigator of the production grant with co-principal investigator Dr. Francesco DeMayo, professor of molecular and cellular biology at BCM. Both Justice and DeMayo are members of the NCI-designated Dan L. Duncan Cancer Center at BCM. Justice is also a lead principal investigator on the phenotyping grant with principal investigator Dr. Richard Paylor, also a professor of molecular and human genetics at BCM.
"We not only have facilities for our own researchers, we can reach out to the world with these facilities," said Justice.
Improving mouse models
"Baylor College of Medicine has developed its knockout mouse expertise and infrastructure over a number of years," said Dr. Paul Klotman, BCM president and CEO. "Dr. Justice has been a leader in this effort and has gathered an impressive team to work with her on this important project that will provide new tools for the understanding of genetics and disease."
"The addition of detailed clinical information for each knockout mouse line will be a boon to disease researchers who want to determine the function of genes and improve mouse models of human disease," said NIH Director Dr. Francis S. Collins. "I am grateful to all of the NIH components who are supporting this effort and to our international partners who have joined us in this scientific endeavor."
Dr. Mark Moore, International Mouse Phenotyping Consortium executive director, said, "We want to characterize each line of mice broadly with no assumptions about what the gene may be doing. If you think of the function of a gene as a needle in a haystack, we're removing the haystack so scientists can see what the needle does.
BCM and its collaborators – the Wellcome Trust Sanger Institute in Hinxton, England, and the Medical Research Council Harwell in Oxfordshire, England – will each receive $34 million over the five-year period and are expected to produce and phenotype (describe the physical characteristics) of 833 strains of knockout mice.
The collaborating institutions have been working in the field of knockout mice for many years. The Sanger Institute was involved in the first phase of Knockout Mouse Phenotyping Project, has been involved in making mouse embryonic stem cell lines, and will supply those to BCM for its work. The Medical Research Council Harwell established the foundation for standardized and broad-based mouse phenotyping. Both groups will speed the research at BCM, Justice said.
Making knockout mice easily available
"Think of this like the genome project," she said, "which increased the speed of genetic sequencing and the availability of genome sequence. This will make knockout mice readily and easily available."
Not only can her group "knockout" a gene in the entire animal, it can do so only in a specific tissue or at a certain point in the animal's life – a process called conditional knockout.
"It helps us create disease models more easily," said Justice.
The project also will focus on the function of mammalian genes.
"We don't know much about the function of genes in mammals at all," she said. "We will follow a gene-by-gene approach and knockout the genes one by one."
Characterizing the physical and other features of the mice that result will give researchers a good idea of what each gene does.
Justice points out that BCM was already well equipped to handle the research in the grant. DeMayo is director of the BCM Genetically Engineered Mouse Core, Justice directs the Mouse ES (embryonic stem) Cell Core Facility, Paylor is director of the Mouse Neurobehavior Core and Dr. Corey Reynolds is head of the BCM Mouse Phenotyping Facility. BCM also has mouse imaging facilities that will speed phenotyping.
A new mouse facility at BCM is highly pathogen-free, which means that the facility could export mice anywhere in the country.
Additional grant recipients
Other groups that received NIH grants include:
- University of California Davis. This center will collaborate with the Toronto Centre for Phenogenomics in Canada, Children's Hospital Oakland Research Institute in Calif., and Charles River Laboratories in Wilmington, Mass.
- The Jackson Laboratory in Bar Harbor, Maine.
These mouse studies build on a long-term understanding of mouse genetics and mouse physiology. Traditionally, scientists generate their own knockout mice to study human disease. However, they rarely study all the physical or behavioral characteristics that go along with the loss of that gene because they are often interested in only one gene. If a researcher can have access to a mouse with a documented phenotype, then he or she can focus research on a particular question rather than spending time and money creating a knockout animal. Once each knockout mouse is phenotyped, researchers can obtain information on what knockout mouse lines are available and how to order them at the University of California Davis KOMP repository.
The 5,000 genes that the Knockout Mouse Phenotyping Project and the International Mouse Phenotyping Consortium will knockout are nominated from the research community. The knockout mice and their normal littermates will undergo extensive testing, including X-rays imaging, MRIs, blood exams, fecal and urine tests, tests of balance and other behavioral exams many times during their lives. Data from these tests will be freely available and researchers can use the data to order knockout mice.
More information on the project is available at NIH.
The 19 NIH institutes, centers and offices contributing to the Knockout Mouse Project are: the NIH Office of Strategic Coordination/Common Fund, 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 Arthritis and Musculoskeletal and Skin Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIDCD, National Institute of Dental and Craniofacial Research, 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 Diseases, National Cancer Institute, and the Office of AIDS Research.
The International Mouse Phenotyping Consortium is a worldwide consortium comprising 16 research institutions and national funders from six countries, including the Medical Research Council (MRC) Harwell (UK), the National Institutes of Health (US), the Wellcome Trust Sanger Institute and EMBL-European Bioinformatics Institute in Hinxton (UK), Helmholtz Zentrum Munich, German Mouse Clinic, (Germany), Toronto Centre for Phenogenomics (Canada), Institute Clinique de la Souris (France), Australian Phenomics Network, RIKEN BioResource Centre (Japan), CNR Monterotondo (Italy), Baylor College of Medicine (US), University of California Davis (US), the Jackson Laboratories (US), Genome Canada (Canada) and MARC - Nanjing University (China).