May 17, 2000 University of North Carolina at Chapel Hill scientists have successfully developed the world's first mice incapable of synthesizing vitamin C, a nutrient essential for growth and healthy bones, teeth, gums, ligaments and blood vessels. The genetically engineered research mice should become a valuable tool in determining vitamin C's role in health and illness, the scientists say.
Dr. Nobuyo Maeda, professor of pathology and laboratory medicine at the UNC-CH School of Medicine, and her colleagues have previously generated mutant mice that showed high cholesterol and atherosclerotic lesions like those found in humans. Such mice now are used widely in research laboratories throughout the world.
"By inactivating a gene that is a key enzyme in ascorbic acid synthesis, we have generated mice that, like humans, depend on dietary vitamin C," Maeda said. "If they don't receive supplementary ascorbic acid, which is another name for vitamin C, within five weeks they become anemic, begin to lose weight and die."
As levels of vitamin C in the mice's blood drop, small but significant increases in their total cholesterol can be measured along with decreases in high-density lipoproteins, the so-called "good cholesterol," she said. But the most striking effects of insufficient vitamin C in the mice are abnormal changes in the wall of the aorta, the main artery channeling blood from the heart to the body.
"Marginal vitamin C deficiency affects the vascular integrity of mice unable to synthesize ascorbic acid, with potentially profound effects on their susceptibility to vascular diseases," Maeda said.
A current, controversial theory about important common illnesses affecting many people such as heart disease and cancer is that oxidative stress may be an important risk factor for disease development, said Dr. Oliver Smithies, Excellence professor of pathology and laboratory medicine at UNC-CH and Maeda's colleague. That is the basis for the opinion that antioxidants such as vitamin C or vitamin E have preventive benefits.
"However, the scientific evidence for this opinion is rather weak, partly because there has not been a good animal model system in which to evaluate it," Smithies said. "Breeding the vitamin C-dependent mice with mice carrying defined genetic mutations will provide numerous opportunities for systematic studies of the role of antioxidants in health and disease."
A report on the continuing research appeared recently in the Proceedings of the National Academy of Sciences.
"Most animals with the exception of humans, some of the higher apes and guinea pigs, can make vitamin C on their own, and so they don't need to eat it," Smithies said. "The value of the mice Dr. Maeda has made is that they are now in a sense 'humanized.' That means experiments with them can combine the dietary things that have long been possible with guinea pigs with the marvelous genetic experiments that are possible only with mice."
Comparable studies of vitamin C could not be done in guinea pigs because guinea pigs do not have the large collection of genetic mutations that interest medical scientists and are available in mice, he said. Vitamin C also is central to development of strong cross linking in binding proteins known as collagen in blood vessels and other tissues. Insufficient vitamin C in humans leads to scurvy and, eventually, death.
Maeda and Smithies have focused on developing animal models for human genetic illnesses for about the past 15 years. Smithies' revolutionary gene-targeting technique, also called homologous recombination, has enabled them and others to create mice that mimic a variety of human disorders, including cystic fibrosis and thalassemia, an inherited form of anemia. One of his former students, Dr. Beverly H. Koller of UNC-CH's department of medicine, led the team that created the world's first animal model for cystic fibrosis, one of the most common genetic diseases of whites.
Gene targeting involves introducing specially designed DNA containing modifications into embryonic stem cells of mice in tissue culture. The resulting genetically altered stem cells are injected into normal mouse embryos, which are then implanted in pregnant mice. "Chimeric" mice are soon born that transmit the altered gene to their own offspring. In this way, researchers can study exactly what the genes control and how drugs and various other treatments affect the mice.
The two scientists have been developing a deeper understanding of the genetic basis of atherosclerosis, commonly known as "hardening of the arteries." The condition involves fatty deposits building up on artery walls and restricting blood flow to the brain, heart and other parts of the body. A complex disease that affects people differently, atherosclerosis is the leading cause of death in the United States, and more than half the population suffers from it eventually.
In their previous work, Maeda introduced mutations into mouse genes affecting fat transport and into genes important for maintaining quality and tone of arteries. Smithies has made key discoveries about the role genes play in high blood pressure. The experiments are enabling researchers to understand better how genetic factors influence essential hypertension, the common yet complex disease called high blood pressure that can lead to heart attacks, stroke, kidney failure and other health problems. He, Maeda and colleagues have also made discoveries about genetic factors that are influenced by aspirin, ibuprofen and other non-steroidal anti-inflammatory drugs.
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