A research team from the University of California, San Diego School of Medicine has identified a defective signaling pathway that contributes to the severity of cystic fibrosis. And their work may pave the way for a new set of therapeutic targets for developers in the field.
The team concluded that mice and cells from patients with cystic fibrosis both have a defect in signaling for PPAR-γ as a result of reduced levels of prostaglandins that activate the receptor.
"Cystic fibrosis results from a genetic mutation in a channel, or membrane pore, that facilitates the transport of chloride and bicarbonate electrolytes from inside the cell to the spaces outside the cell," says lead investigator Gregory Harmon. "Loss of the cystic fibrosis pore channel results in inflammation and mucus accumulation. It also results in dehydration of the cell surfaces that make up the lining spaces inside the lungs and other affected organs, such as the intestinal tract."
When the researchers treated mice with cystic fibrosis with the drug rosiglitazone, a thiazolidinedione drug that binds and activates PPAR-γ, gene expression was largely normalized and survival improved. The drugs also corrected part of the inflammatory process in the tissue. Deleting the PPAR-γ protein in the intestine of mice worsened the disease, leading to mucus accumulation in the intestine.
Cystic fibrosis afflicts one in every 3,000 people and leads to progressive lung failure, pancreatic failure and gastrointestinal obstruction. Victims live to an average age of 40.
- check out the press release from UC San Diego