Zebrafish model leads to discovery of a molecule that regulates heart size

Scientists from the University of Pittsburgh have made a significant discovery that may lead to many new potential applications in the field of medicine. Using zebrafish as model animals, they were able to accurately pinpoint an enzyme inhibitor that allows for a large increase in the number of progenitor cells inside the developing heart, which, in turn, increases its size considerably.

Zebrafish were selected for the new investigation because of their similarities to humans. In addition, these vertebrate animals have transparent embryos that develop rapidly, are small and easy to handle, and develop outside their mothers. As senior author Michael Tsang, Ph.D., assistant professor, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, notes, using the zebrafish model has "powerful advantages" for studying embryonic development. "This gives us a better understanding of heart development during the embryonic stage and has implications for adult disease," he says. "As we try to create treatments that restore normal function to damaged or diseased tissues, it will help us to know the biologic pathways and signals that formed these organs whole and healthy in the first place. This information can be gained by studying developmental biology."
Using a line of transgenic zebrafish that the team had previously modified to express the gene for a green fluorescent protein associated with a key signaling pathway of fibroblast growth factors (FGF), the experts observed the actions of some important factors involved with the embryonic development process. "The transgenic zebrafish embryos allow us to actually see when a drug or compound influences FGFs because the cells glow green," notes Dr. Tsang. "The embryos are like biosensors for FGF signaling, showing us what's happening in real time in living animals."

Dr. Tsang explained that the FGF signaling inside the model animals was hyperactivated by a small molecule called BCI. This occurred because BCI inhibited the action of the feedback regulator Dusp6, an enzyme that typically plays a role in reducing the FGF signal in the average embryo. By manipulating the levels of BCI, the researchers were able to obtain less FGF inhibition. This ultimately led to the resulting embryos having larger hearts. In addition, says Dr. Tsang, "Unraveling the fibroblast growth factor pathway has broad implications for improving wound healing as well," noting that FGF2 has been used to treat chronic skin ulcers following burn surgeries in Japanese patients. Thus, he says, "BCI alone or in combination with FGF2 might accelerate the healing process and improve wound repair." The findings were published in an advanced online version of Nature Chemical Biology.

The scientists are now working on devising a way to translate their findings into humans and on developing potential therapeutic uses for the molecule.

News Release: Pitt team finds molecule that regulates heart size by using zebrafish screening model http://www.eurekalert.org/pub_releases/2009-07/uops-ptf_1070209.phpJuly 5, 2009