Northwestern Receives $17 Million for Functional Genomics Research

EVANSTON, Ill. – Northwestern University has been awarded one of its largest research grants in history, a $17 million, five-year grant from the National Institutes of Health (NIH) for a major new research initiative in genetics and functional genomics.

The research at the new NIH Neurogenomics Center at Northwestern could lead to a more complete understanding of the human nervous system and behavior, including neurological disorders ranging from Alzheimer’s disease and addiction to blindness and sleep disorders.

"The timing of this project is perfect," said center director Joseph S. Takahashi, who cloned the first mammalian circadian gene, Clock, in 1997. "Our work will be very complementary and synergistic with the information being produced by the Human Genome Project."

The Northwestern center is one of three such centers in the country. Researchers will utilize mutations in mice and genome-wide screening methods to identify genes responsible for behaviors such as learning and memory, vision, circadian rhythms, the propensity to become addicted, sensitivity to stress and the development of anxiety.

Takahashi, professor of neurobiology and physiology and a member of the neurology department at the University’s Medical School, expects the center’s findings to provide information useful for understanding the sequence of the human genome and for developing new bioinformatics databases and tools to interpret the genome.

The center will be housed at Northwestern, as part of the University’s new Center for Functional Genomics, but will operate in conjunction with collaborative sites at Columbia University, Duke University and the University of Iowa. Eric R. Kandel, who won the Nobel Prize in Medicine last year, will lead the effort at Columbia, with Marc G. Caron, professor of cell biology, at Duke and Val C. Sheffield, professor of pediatrics, at Iowa.

Co-investigators from Northwestern are Jon E. Levine, Lawrence H. Pinto, Fred W. Turek and Martha H. Vitaterna from the department of neurobiology and physiology, and Warren A. Kibbe and Eva Redei from the University’s Medical School.

The researchers will employ a genetic technique known as genome-wide mutagenesis. A chemical called ENU (N-ethyl-N-nitrosourea) is used to create a broad spectrum of random mutations, single base pair changes in DNA, that are passed on to subsequent generations.

"For many diseases and behaviors, humans and mice are very similar – the corresponding genes have similar functions," said Takahashi, who also is an investigator in the Howard Hughes Medical Institute. "In humans, more than 35 percent of the genes have unknown functions, and a good number of these genes are likely to be important for the function of the brain. This gives us an opportunity to discover new genes critical to the nervous system in the mouse, which will contribute to our understanding of the human system."

The approach being used by the center, called forward genetics, in which the animal’s behavioral change leads to identification of the responsible genes, has been shown to be powerful and productive. Once there is evidence of a single gene mutation, scientists can identify the gene using positional cloning.

Takahashi’s laboratory was the first to use the ENU technique to identify a mouse with a behavioral problem, in this case a problem with its circadian clock. The use of forward genetics led to the identification in 1994 and the cloning in 1997 of the mammalian circadian gene, Clock. Last year, the lab used similar methods to identify casein kinase I epsilon as the first enzyme target for circadian rhythms in mammals.

Using a battery of high-throughput tests, Northwestern researchers first will screen the mice for specific behaviors, such as response to light and the timing of activity and rest, and identify those that fall into one of the five areas of interest. Researchers at all four collaborating institutions will then study the mice that fall into their areas of expertise, looking more closely for abnormalities in nervous system function and behavior.

These follow-up studies will utilize Northwestern’s expertise in circadian rhythms and the neuroendocrinology of stress and anxiety, Columbia’s expertise in learning and memory, Duke’s expertise in the mechanisms of drug addiction and Iowa’s expertise in vision.

In addition to producing mice for study by the center’s researchers, the center also will act as a national resource, distributing up to 50 new mouse models per year to the scientific community as well as providing rapid access to the analyses of the center’s mice. The bioinformatics core will be based at Northwestern.

"Based on rapidly developing genomic and genetic tools, the mouse is becoming a unique model for understanding mammalian neurobiology," said Steven M. Hyman, director of the National Institute of Mental Health (NIMH), the institute awarding the grant for the new NIH center.

"This project will provide critically important opportunities to systematically identify genetic alterations that affect brain circuitry, and therefore behavior. This information will provide a much needed platform for the development of better animal models for serious disorders of the nervous system, such as schizophrenia, mood disorders and autism."

In addition to NIMH, co-funding is provided by the National Institute on Deafness and Other Communication Disorders, the National Institute of Environmental Health Sciences, the National Eye Institute, the National Institute on Aging and the National Institute on Drug Abuse.

4/17/01