Transgenic Mice Created By Researchers May Shed Light On Human Heart Disease

January 26, 1998

A University of Colorado at Boulder research team has created several strains of transgenic mice that carry gene mutations for a heart disease that has been shown to be the leading cause of sudden death in young athletes.

Known as hypertrophic cardiomyopathy, the genetic disease is marked by significant thickening of the heart muscle, said Leslie Leinwand, chair of CU-Boulder's molecular, cellular and developmental biology department who is spearheading the research effort. The disease can obstruct blood flow in heart ventricles, lessening their ability to pump blood into the arteries.

"This is a difficult disease to diagnose," said Leinwand. "While symptoms can include shortness of breath, dizziness and chest pain, often the first sign of the disease is death."

Although the most frequent cause of the disease has been shown to be a mutation on a tiny portion of a single gene that produces the protein myosin, it is not known why the myosin gene causes mortality, she said. "We have created these transgenic mice to help us understand the biological processes and hopefully test new therapeutic agents."

Myosin is a major component of muscle tissue and "molecular motor" that creates the energy and motion to allow heart contractions to occur.

Healthy humans have two copies of the normal gene for myosin while people with the disease have a mutated form, just as the mice do, said Leinwand. To create a transgenic mouse, the researchers added a mutated myosin gene to the genetic material of a normal mouse, which was taken up randomly by one of its chromosomes.

In humans and mice, healthy heart muscle is very organized and densely packed with structural protein that allows it to contract, she said. But in heart muscle carrying the mutant form of the myosin gene, the normal, parallel alignment of muscle cells is lost and the cells appear disorganized.

Although people with hypertrophic cardiomyopathy often have larger hearts than normal people, the hearts of most athletes enlarge normally due to rigorous exercise, making the condition more difficult to detect, she said. The research project is funded primarily by the National Institutes of Health.

The CU-Boulder team also has created a mouse that carries a mutant gene for the protein troponin T, which is related to the sensing process of tiny muscle fibrils located in the heart. Although mutant troponin T genes cause little or no heart enlargement, the production of even small amounts of the protein by mutant genes causes a high incidence of sudden death, she said.

"In troponin mutant mice, we can manipulate how much of the protein they make," she said. "We have found that when the gene makes even a small amount of the protein, it can cause death within eight hours."

The team exercises the transgenic mice on a custom-built treadmill in the department's new, $1.5 million, pathogen-free Center for Mammalian Biology in an effort to measure their heart responses to vigorous exercise. "This kind of research is new to the Boulder campus," said Leinwand, who noted the new tools and techniques now available in mammalian biology play a major role in the application of basic knowledge to human welfare.

Leinwand and her collaborators, who have patented their mutant myosin transgenic mice through the University Technology Corp., recently co-founded a university spin-off company called Myogen to search for new ways of treating hypertrophic cardiomyopathy in humans. "We are looking for ways to improve the motor activity in the heart muscles," she said. "The answer may turn out to be a therapeutic agent."

Leinwand has had preliminary discussions with a major pharmaceutical company to pursue possible therapetic drug screening projects. Leinwand's team includes MCDB research associate Karen Vikstrom, cardiologists Dr. Jil Tardiff and Dr. Setsuya Miyata as well as several graduate students. The current study involves about 1,000 mice.

University of Colorado at Boulder

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