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Searching for mouse models of human



Dabney Johnson watches a mutant mouse.

The lowly mouse is highly regarded as a key to solving a number of medical mysteries. The mouse has long been known to be genetically similar to the human. The recently obtained drafts of the human and mouse genomes suggest that the two genomes are 85% identical: The differences involve a few hundred of the approximately 35,000 genes in both organisms. From an economic standpoint, mice and rats are small and inexpensive to maintain, so it is not surprising that they are used in 90% of the research involving animals.

Many mice born with mutations in at least one gene are good models for human diseases. For example, some mutant mice produced by former ORNL geneticist Ray Popp have sickle-cell anemia. They are being studied as models of the human disease at Meharry Medical College, a historically black institution and a participant with ORNL in the Tennessee Mouse Genome Consortium (TMGC).

When a mouse is a model for a human disease, different treatments can be tested on it. Treatments found to control or cure the disease in the mouse could lead to the development of a therapy that works in humans with a similar disease.

Not all mouse models of human disease are perfect yet they may still be useful, according to Dabney Johnson, head of the Mammalian Genetics and Genomics Section in ORNL's Life Sciences Division. "Children with cystic fibrosis die of lung problems, whereas mice with CF die of intestinal blockages. Mice with the CF gene can survive if put on a liquid diet. Perhaps mice have a gene that makes a protein that enables them to compensate for the lung disorder caused by the CF gene. If so, knowledge of the structure and function of this protein could be the key to developing a drug that could benefit humans with CF."

To determine whether ORNL's mutant mice are good models for human diseases of the central nervous system (CNS), Johnson is collaborating on projects with the partners of TMGC. The TMGC recently received a $12.7 million grant from the National Institute of Mental Health (NIMH) to create 25 to 50 new strains of mutant mice that will be used to study neurological disorders. The partners include the University of Tennessee at Knoxville, UT-Memphis, St. Jude Children's Research Hospital, Vanderbilt University, and Meharry Medical College. The TMGC is interested in mutations leading to new genetic information about neurological conditions ranging from Alzheimer's and Parkinson's diseases to depression and addiction.

"We produce mutant mice by treating males with the powerful mutagen ENU (ethylnitrosourea), mating them with females with particular genetic characteristics that help trace the newly induced mutations, and screening their descendants for disorders in the brain and central nervous system," Johnson says. "The screening is done using several tests. For example, mice are placed on a spinning rod to see how well they can maintain their balance there before falling off. Mice having certain mutations lack the coordination and balance of normal mice and fall off this rotor-rod more quickly. We can detect whether a mouse is depressed by observing its behavior in a swimming test. If it tends to float rather than swim vigorously to try to get out of the water, we classify it as a depressed mouse.

"An activity test is used to determine if a mouse is underactive or overactive as a result of a CNS mutation. In this test to gauge a mouse's activity in a box, a photobeam sensor counts the number of times per minute that a mouse interrupts light beams sent across the box."

Johnson and her associates also use this test to measure a mouse's anxiety level. Mice are, by nature, anxious creatures. "A normal mouse stays near the wall where it is more protected rather than going to the middle of the box where it would be out in the open and feel more exposed to predators," she says. "A less anxious mouse, one that is calmer than the normal mouse and, therefore, likely to have a CNS mutation, ventures forth into the open space."

Johnson's group also uses an array of tests to measure learning abilities and memory in mice to screen for CNS mutations. For example, the researchers administer a mild foot shock and play a sound at the same time. A day later, when a normal mouse hears that sound, it will freeze in fear that the unpleasant shock may occur again. Mice with certain CNS disorders will ignore the sound and continue their activity.

As a part of that same test, a normal mouse returned to the same box 24 hours later will recognize the box as the site of the shock and freeze. However, a mouse with a CNS disorder will be just as active in the box as it was 24 hours before, prior to the administration of the shock. The two parts of this test measure two different kinds of memory.

Another CNS test is the startle test. "A normal mouse will have a measurable startle response when it hears a loud noise," Johnson says. "It will flinch, and this action will be detected by a load sensor. But an abnormal mouse may not startle at all, perhaps because it is deaf. Or a mouse with a CNS disorder could startle too much rather than simply jump or flinch."

The TMGC partners help ORNL screen mice for new mutations and analyze confirmed mutations in more detail. One new mutation recently discovered by ORNL's Eugene Rinchik causes the mouse born with it to have continuous seizures. Mice with this mutation have been sent to consortium researchers who then conduct studies to determine if the cause of the seizures is neurochemical or neurophysical. They will try to determine if this "seizure" mouse is a good model for some form of human epilepsy.

At ORNL, researchers run automated analyses of blood and urine samples from mice, measuring their white and red blood cell counts and hemoglobin concentrations. The dip stick urine test is used to measure for sugar concentration and excess protein. This information tells the researchers whether mice are anemic or diabetic or suffer from infections, leukemia, or blood-clotting problems typical of hemophilia.

"Copies of our mouse mutants go to UT at Memphis, which screens mice for mutant genes that cause addiction to alcohol and drugs such as cocaine," Johnson says. "For example, our mice are given the two-bottle test in which one bottle contains water and the other, alcohol. A mouse with a genetic predisposition for alcoholism might drink from the alcohol bottle when thirsty, but a normal mouse drinks only from the water bottle. A normal mouse injected with alcohol falls off the rotor-rod quickly, and it loses its inhibitions and shows less anxiety-like most people who have too much to drink."

Mice suspected of having CNS disorders, based on ORNL tests, are sent to the UT Memphis Health Sciences Center. The mice are sacrificed and their brains are sliced, stained, and studied to determine if they have an abnormal anatomy. The eyes of these mice are also examined to determine whether the retina, neural connections, and other components are formed normally. Researchers also check eye samples for signs of macular degeneration and other predictors of impaired vision.

For many people, mice can be a nuisance, but the results obtained from research using mice could give victims of some diseases a new lease on life.

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