Developmental biologists at the University of Pittsburgh have been chosen to participate in a $100 million federal "Bench to Bassinet" network that is dedicated to learning about the formation of the cardiovascular system and applying that knowledge to create new diagnostic and intervention strategies for congenital heart disease.
The Pitt team, led by Cecilia Lo, Ph.D., chair of the Department of Developmental Biology, School of Medicine, will use the mouse as a model system to identify and describe the core set of genes that play an essential role in producing structural heart defects, which include holes in the heart walls, transposition of major blood vessels that connect to the heart and other problems of cardiac development that can affect up to 1 percent of live births.
"Ultimately, we want to build a diagnostic chip that can rapidly and accurately identify the genetic root causes of specific heart defects," Dr. Lo explained. "That could enable us to examine how these genes influence disease progression, correlate them with long-term outcomes and better tailor treatment."
To find the genetic determinants of congenital heart disease, her $8.6 million project will expose fetal mice to a chemical that increases the likelihood of gene mutations and use non-invasive fetal echocardiography to spot any heart defects that result. Then the DNA of the affected mice will be examined to identify the gene changes that caused the abnormality. A zebrafish model will be used as a quick bioassay to validate the findings.
Dr. Lo is particularly interested in mutations that affect the function of cilia, which are hair-like projections on cells that are best known for moving fluids along tissue surfaces. "We now know cilia are critical to heart development in the fetus," she said. "For example, they help to correctly orient the heart, which is a left-right asymmetrical organ. This asymmetry is crucial for normal functioning and allows for efficient oxygenation of blood."
One of a handful of similar academic departments nationwide, the Department of Developmental Biology was established in April at the University of Pittsburgh School of Medicine and Dr. Lo was named its founding chair.
"As the Bench to Bassinet commitment indicates, the study of fetal organ and tissue development will not only teach us about fundamental biological principles, but also could yield the treatments of the future," said Arthur S. Levine, M.D., dean of the School of Medicine and senior vice chancellor for the health sciences at Pitt. "Dr. Lo's research techniques also can be applied to similar exploration of birth defects in other organ systems."
The Bench to Bassinet program was devised by the National Heart, Lung, and Blood Institute, which is part of the National Institutes of Health. Dr. Lo's project is in the Cardiovascular Development Consortium, which includes research teams from the University of Utah, Harvard University and the University of California, San Francisco. Another consortium comprising five research centers will focus its work on translational research in pediatric cardiac genomics. Both will work with an existing clinical pediatric heart disease network.
"Congenital heart defects are the most common and life-threatening problem for newborns in the United States," said NHLBI director Elizabeth G. Nabel, M.D. "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."
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