A $16.3 million, five-year grant from the National Institutes of Health will fund a major new research program at The Jackson Laboratory (TJL) to increase the number and availability of mouse models for human neurological diseases, such as epilepsy, addiction, and neurodegenerative disorders.
The federal grant -- the largest single grant award in the Laboratory's 71-year history -- will fund a Neuroscience Mutagenesis Facility to create at least 50 new mouse models a year in neural disease areas including motor function, epilepsy, obesity, hearing, vision, learning, and memory deficits. In addition to boosting research at the Laboratory, the program will provide scientists worldwide with unrestricted access to the new resources.
Headed by neurogeneticist Dr. Wayne Frankel, a TJL staff scientist, the new program will involve collaborations with investigators from within the Laboratory and from other institutions, including the Monell Chemical Senses Center, University of Pennsylvania, University of Vermont, and Northern Illinois University. Dr. Kevin Seburn, a Research Scientist at TJL with expertise in neuromuscular physiology, is supervisor.
"This new program is truly ground-breaking. Our hope is that it opens the way for entirely new research approaches in gene discovery directed at understanding, treating, and preventing a wide range of devastating neurological and psychiatric disorders," says Director Dr. Kenneth Paigen. "It comes from a unique combination of expertise here in neurobiology and mouse genetics, and introduces sophisticated new techniques for detecting abnormalities in mice."
There is a growing collection of mouse strains that have provided insight into the function of mammalian genes in the central nervous system. However, research has been limited by an insufficient number of models whose appearance or behavior (i.e., phenotype) suggests specific neurological conditions found also in humans. A major goal of the NIH-funded initiative at The Jackson Laboratory is to address this so-called "phenotype gap" in using mice for the study of human neurological disease.
Key to the program is a powerful genetic tool known as genome-wide mutagenesis. By treating mice with a chemical -- ENU (N-ethyl-N-nitrosourea) -- researchers induce a large number of random point mutations in the DNA of stem cells in mouse sperm. These mutations cause a wide range of disease phenotypes in offspring of the male mice.
An important feature of the program is the incorporation of new developments in mutagenesis technologies, such as treatment of mouse embryonic stem cells with chemical mutagens other than ENU, based on recent work by TJL Staff Scientist Dr. John Schimenti. These improvements will broaden the range of "target" genes and result in more efficient production of mutants.
Hand-in-hand with the mutagenesis process is "high-throughput" screening to quickly identify mutations, and a second-stage "focused" screening for abnormalities in nervous system function and behavior. Dr. Seburn and his colleagues are pioneering systems and techniques to automatically measure such phenotypes as muscular strength, balance and coordination, sensory function, learning, anxiety, seizure susceptibility, hearing defects, ingestive behavior, activity, and metabolic performance. The ability to measure phenotypes over time will enable a unique feature of the new program: finding models for mid-to-late onset neurological disorders, such as those that occur with aging.
"The study of spontaneous mouse mutations has already revolutionized the way biomedical research is done, together with the Genome Project providing the tools for gene discovery," says Dr. Frankel. "But spontaneous mutations arise infrequently and tend to hit the same genes over and over again, those that are easily mutated and whose unusual appearances are readily noticed by animal caretakers. The combination of chemical mutagenesis with dedicated, state-of-the-art physiological screening will give the scientific community new types of mouse models to study."
CONTACT: Public Information
207-288-6051
pubinfo@jax.org
The particular areas of neuroscience covered by the Neuroscience Mutagenesis Facility reflect the scientific expertise of Laboratory staff and their collaborators, and the research priorities of the NIH institutes sponsoring the program. Those sponsors include the National Institute of Neurological Disorders and Stroke, National Institute of Aging, National Institute on Deafness and Other Communication Disorders, National Institute of Drug Abuse, National Eye Institute, and National Institute of Alcohol and Alcoholism.
The Neuroscience Mutagenesis Facility will be housed on the third floor of the Laboratory's new Genetic Resources Building, scheduled for initial occupancy later this year. Funding sources for that facility include the National Institutes of Health, Kresge Foundation, Howard Hughes Medical Institute, National Science Foundation, Hannaford Charitable Foundation, The Libra Foundation, Fannie E. Rippel Foundation, The Ellison Medical Foundation, and Pentagoet, a Maine family foundation.