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SALT LAKE CITY—In a major initiative to eradicate congenital heart defects in children, the National Institutes of �ǿմ�ý (NIH) has awarded University of Utah medical researchers an $8.2 million grant to study heart development in a way that has never been done before – by examining the entire genome of the developing heart.

The six-year grant, issued through the National Heart, Lung, and Blood Institute (NHLBI), gives Joseph Yost, Ph.D., Professor of Neurobiology and Anatomy and of Pediatrics, funding to establish the zebrafish Cardiac Development Research Center, one of four national centers being set up to study heart developmental defects. The three other centers are at Harvard, the University of Pittsburgh, and The University of California, San Francisco, all of which will use mouse models for their studies. Collectively, the four centers are called the Cardiovascular Development Consortium (CvDC).

The CvDC is part of is part of a massive $100 million NIH effort called the Bench to Bassinet program, which also establishes consortiums of human genomics and clinical centers. The goal of Bench to Bassinet is to foster basic science and clinical research that produces discoveries and therapies to treat or eliminate congenital heart defects, the No. 1 killer of children under age 1.  

By using zebrafish for their studies, U of U researchers can gain a genomewide perspective of the developing heart, which will be a first, according to Yost. “Researchers have studied heart development one gene at a time, and that has given us a lot of progress,” he said. “But it’s time to look at the whole genome of the developing heart. Through our zebrafish center, we will be able to look at every decision point of every gene during the process of building a functioning heart.”

The zebrafish is a tiny, tropical minnow that makes an excellent model for studying human biology for several reasons:

 • Their genome is very similar to that of humans, meaning they have many analogous genes.
 • They are prolific breeders, with short gestation periods; females can produce 200 offspring a week, allowing researchers to examine thousands of related fish at different stages of heart development at the same time.
 • They are transparent during development, making it possible to actually see organ formation and function by using fluorescent genes.

Yost plans to investigate both the normally and abnormally developing heart at distinct steps in development. As part of this, he’ll introduce 100 or more gene mutations to observe how individual mutations influence the networks that regulate the 22,000 genes involved in zebrafish heart development. He also plans to investigate how mutations affect various aspects of heart physiology, such as the electrical current that controls heart beat.

Yost’s co-investigators on the project are Bradley R. Cairns, Ph.D., professor of oncological sciences and an investigator with the U of U’s Huntsman Cancer Institute, and Martin Tristani-Firouzi, M.D., a pediatric cardiologist and associate professor of pediatrics. Cairns will head up a bioinformatics effort to use computer-based analyses of genomewide data. Tristani-Firouzi will lead the part of the study that looks at heart physiology. By comparing normal and aberrant developing hearts, the researchers expect to uncover the molecular signatures of heart defects. This multilayered molecular profiling of heart development has not been performed in any organism to date, according to Yost.

“The kinds of things we are doing in zebrafish, can’t be done in other model systems,” he said. “We can ask what’s happening with every gene in the developing heart.”

As the centers in the CvDC and genomics consortium identify candidate genes related to heart defects, they’ll incorporate them into the molecular profiling to rapidly obtain genomewide molecular signatures. That information then will be made available to all the centers for comparisons between zebrafish and other species to identify the common molecular signals relevant to human developmental heart defects.

“Congenital heart defects are the most common and life-threatening problem for newborns in the United States,” said Elizabeth G. Nabel, M.D., director of the NHLBI, which is part of the National Institutes of �ǿմ�ý. “Our Bench to Bassinet research efforts will offer new insights into how the human cardiovascular system develops and help speed the transition of promising laboratory discoveries into treatments that can save young lives.”

Multidisciplinary collaboration will play a critical role in the project, according to Yost. “The idea is to get basic scientists and clinicians working together to bring the full force of science to figure out what causes heart defects in kids,” he said. “There will be a lot in information sharing among basic science and clinical researchers at both the local and national levels.”

The first year of the grant primarily will be one of planning, although Yost expects the zebrafish center to be up and running by July of 2010. Once the project is fully operational, his team will receive more than $1 million annually for five years.

To staff the center, Yost expects to recruit researchers in the basic sciences, students, technicians, and physicians. The Primary Children’s Medical Foundation contributed some seed money to get the project rolling.

Although it’s hard to predict what breakthroughs may come from this major national effort, Yost believes it will result in findings that aid patients. “We want to understand how the whole genome works as a network to build a properly functioning heart,” he said, “and then use that knowledge to find ways to treat and cure children with congenital heart defects. There certainly will be some new insights into how to treat kids.”