Research on mice may help explain why humans become addicted.
Do differences in response to stress drive people to drink alcohol or take illegal drugs to the point of becoming addicted? What is the relationship among genes, gut microbes and intestinal disease? Why are some people more sensitive to pain than others?
These are some of the questions being addressed by a national group of researchers in collaboration with Oak Ridge National Laboratory geneticists in the Collaborative Cross project. ORNL's mouse genetics research facility, the William and Liane Russell Functional Genomics Laboratory, is the North American site of the Collaborative Cross. The laboratory houses the ultimate reference mouse population that models the diversity of humankind and provides a unique tool for understanding human disease and testing potential treatments.
The ORNL laboratory is a pathogen-free facility with cryogenic storage that contains 18,000 mice with space for up to 80,000. The state-of-the-art facility, which opened in 2004, began hosting the Collaborative Cross project in May 2005.
"Biologists usually work on small projects, but Oak Ridge has the big science project experience to host a large-scale biology user resource," says Elissa Chesler, project manager for the Collaborative Cross and leader of ORNL's systems geneticists. "ORNL offers the added benefit of high-performance computing to manage and analyze data from the mouse experiments."
Chesler says that the biology community is excited now that more than 9,000 mice bred for the Collaborative Cross project are available for experiments. The project has attracted funding from the Ellison Medical Foundation, the Department of Energy and the National Institutes of Health.
The ORNL team is collaborating with Virginia Commonwealth University in looking for connections between anxiety and alcoholism. Better understanding could lead to treatments for both disorders. The study recently identified a region of a mouse chromosome that appears to alter significantly the effects of alcohol on anxiety.
Not surprisingly, as the work progresses, new questions arise concerning the role of stress in alcohol addiction. Do alcoholics have an abnormal stress response? Does the same genetic variation that causes stress also cause alcoholism? Do people drink for different reasons?
Chesler evaluates a variety of studies about the genetics of mouse behavior. Her colleagues have found that many mice dislike the taste of grain alcohol commonly used for alcohol addiction tests. She now is collaborating on a genetics study of mice that consume beer, which has a taste more palatable than the stronger alcohol. She says mice show high levels of stress when picked up by humans and placed in commonly used memory tests, suggesting that traditional ways of handling and testing mice probably should be modified in the Collaborative Cross.
With members of the microbial ecology group, Chesler is examining whether genetic variation in Collaborative Cross mice contributes to differences in the composition of bacteria in mouse intestines. Gut microbes have been shown to influence diet, sensitivity to pain, inflammation, Crohn's disease and Celiac disease.
In one mouse study at ORNL conducted with the University of Pittsburgh School of Medicine, researchers look for genes that cause some people to be more sensitive to pain than others. The goal is to identify ways to design new drugs for more effective treatment of unique types of pain.
For years geneticists have sought a better research tool for understanding complex human traits—such as obesity, rates of aging and pain sensitivity—that are influenced by multiple genes and their interactions with the environment. Researchers have long desired an ultimate reference mouse population, not one bred from historic research populations derived from "pet" mice. "Those mice traditionally were selected based on a behavioral trait rather than randomly," Chesler explains.
The Collaborative Cross, proposed in 2001, uses a rigorous breeding scheme to maximize the genetic diversity of inbred strains of mice. Aided by software developed by Ken Manly, a visiting scientist from the University of Buffalo, eight "founder" mice with eight different genomes have been randomly bred at ORNL. Ultimately, through years of inbreeding, a thousand different strains of mice will be generated, perhaps providing answers to some of humankind's most intriguing questions. —Carolyn Krause
Contact: Elissa J. Chesler
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