ScienceDaily (Mar. 10, 2009) — "Researchers at the University of Pennsylvania School of Medicine have unlocked the mystery of a puzzling human disease and gained insight into cardiovascular development, all thanks to a big-hearted fish."Cerebral Cavernous Malformations (CCM) are abnormal clusters of leaky blood vessels, typically in the brain, which can cause both seizures and strokes. The genes CCM1, CCM2, and CCM3 had previously identified by researchers as responsible for the disease, yet their functions were uncertain.
It was discovered that mutations in CCM1, CCM2, or HEG caused zebrafish to develop enlarged hearts. Mark Kahn, MD, Associate Professor of Medicine, graduate student Benjamin Kleaveland, and colleagues sensed that this could help unlock the mystery of what CCM proteins do and extended it to testing on mice.
"Our notion was to take the zebrafish developmental studies and use the mouse as a way of bridging between what appeared to be a role in heart development in fish and blood vessel disease in people," says Kahn.
Kleaveland genetically engineered mice that both completely lack the HEG protein and produce diminished amounts of CCM2. This combination of genetic defects is fatal for the mice; they die during embryonic development. But, examination of their cardiovascular system and that of genetically altered fish, as well revealed several key findings:
1. Loss of HEG produces cardiovascular defects in the heart, in blood vessels in the lung, and in the lymphatic system.
2. Loss of HEG with partial loss of CCM2 produces a worse cardiovascular defect
3. Defects are characterized by malformed cell-cell junctions in the endothelial cells that line these organ
4. HEG actually physically interacts with CCM proteins
"It looks like the disease is a reflection of a disruption in endothelial cell-cell junctions, and this pathway is required to regulate them," Kahn says.
The study also addresses a debate in the field as to whether CCM is the result of defects that cause the disease present in the affected endothelial cells themselves, or in the cells that surround them, such as neurons in the brain?
"We think the developmental model has shown us that the requirement is in the endothelial cell," he says.
Student ID: 42095547
Reference:
Big-hearted Fish Reveals Genetics Of Cardiovascular Condition
http://www.sciencedaily.com/releases/2009/02/090225132534.htm
