( proteins that ERAD deploys to seek out...)Johns Hopkins lab scientists tame overactive CF protein

"We were able to confirm that to get rid of the defective CFTR protein, cells deploy VCP/p97 protein, which latches onto the damaged CFTR and sends it to the proteasome for destruction," Zeitlin says. "Using RNA interference, which basically works by silencing the expression of genes or proteins, we homed in on VCP and blocked its production. That let the defective CFTR to successfully sneak past the quality control and race up to the surface."

To determine VCP's role in the destruction of CFTR, researchers compared bronchial cells from CF and non-CF patients. In non-CF cells, the protein's levels were in check, whereas they were strikingly high in cell samples obtained from CF patients.

Suspecting that inhibiting VCP would spare the chloride-transporting channels from premature demise, the team showed that when the VCP's level was lowered, it no longer destroyed CFTR.

In a second set of tests, researchers blocked the destruction of CFTR with a proteasome-inhibiting drug currently used to treat multiple myeloma. Silencing the protein by the use of RNA interference was superior to the proteasome inhibitor, researchers found.

Both the drug and RNA interference also staved off inflammation caused by cytokine IL8, which is the main inflammatory chemical produced by CF damaged cells.

"Targeting VCP, we were able to achieve two things at once -- restoring chloride channel function and curbing inflammation" says co-author Neeraj Vij, Ph.D., a postdoctoral fellow at the Children's Center. "Inhibiting specific sites in VCP can lead to the development of CF drugs."

"The goal is to develop small molecules that disrupt the binding between the VC protein and CFTR, much like tiny guided missiles that take out portions of this rampant VC protein before it latches onto CFTR," Zeitlin says.