Navigation Links
Johns Hopkins lab scientists tame overactive CF protein

A team led by Johns Hopkins Children's Center scientists has identified and successfully tamed an overactive protein that plays a key role in cystic fibrosis (CF), a genetic disorder that interferes with the body's ability to transport chloride in and out of cells.

Using a tool called RNA interference on cells in the laboratory, researchers successfully intercepted signals sent out by the rampant protein and prevented cell damage by the protein, effectively restoring the cell to normal.

"The hope is that these findings will be used to design therapies and drugs that go beyond symptom management and actually restore normal cell function to prevent CF," says senior investigator Pamela Zeitlin, M.D., a pulmonologist at the Children's Center, although she warned that they are years from developing or testing such treatments in whole animals or people. A report on the work from scientists at the Children's Center and the University of Maryland appears in the June 23 issue of the Journal of Biological Chemistry.

The overactive protein, called VCP/pr 97 (valosin containing protein), kills a chloride transporter in the cells of the vast majority of CF patients, but quieting the protein restores the cells' ability to transport chloride in and out, researchers found. The inability to transport chloride is the hallmark of CF that causes dangerous buildup of thick, sticky mucous in several organs, including the pancreas and the lungs, leading to malnutrition, chronic lung infections and lung damage.

Cells have a built-in quality-control machinery called ERAD (endoplasmic reticulum-associated degradation), which chemically "marks" defective proteins for destruction and sends them to the cell's waste-disposal complex, called the proteasome. In people with CF, defects in genes for a protein called CFTR (cystic fibrosis transmembrane regulator) interrupt the transport chemistry. Until now, researchers had not identified the precise search-and-destroy proteins that ERAD deploys to seek out the mutant CFTR.

"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.


'"/>

Source:Johns Hopkins Medical Institutions


Related biology news :

1. Johns Hopkins flu expert calls for mandatory vaccination of health care workers
2. Whole-genome study at Johns Hopkins reveals a new gene associated with abnormal heart rhythm
3. Johns hopkins researchers find link between cells energy use and genome health
4. Hopkins AIDS experts issue warning about global efforts to provide drug therapies
5. Hopkins scientists uncover tags that force proteins to cell surface
6. Hopkins researchers discover genetic switch that turns off an oxygen-poor cells combustion engine
7. Hopkins study suggests commercially available antibiotic may help fight dementia in HIV patients
8. Hopkins researchers develop new tool to watch real-time chemical activity in cells
9. Hopkins scientists show hallucinogen in mushrooms creates universal mystical experience
10. Hopkins researchers discover how brain protein might control memory
11. Hopkins scientists link immune response to ghost parasites and severely congested sinuses
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:12/20/2016)... and GENEVA, Dec, 20, 2016   ... data sensor technology, and STMicroelectronics (NYSE: ... spectrum of electronics applications, announced today the launch ... kit for biometric wearables that includes ST,s compact ... Valencell,s Benchmark™ biometric sensor system. Together, ...
(Date:12/15/2016)... and BADEN-BADEN, Germany , December 15, ... global financial services provider, today announced an agreement with NuData ... biometrics, to join forces. The partnership will enable clients to ... in compliance with local data protection regulation. ... In order to provide ...
(Date:12/15/2016)... 14, 2016 "Increase in mobile transactions is ... mobile biometrics market is expected to grow from USD ... 2022, at a CAGR of 29.3% between 2016 and ... the growing demand for smart devices, government initiatives, and ... "Software component is expected to grow at a high ...
Breaking Biology News(10 mins):
(Date:1/11/2017)... ... January 11, 2017 , ... Photonics industry ... photonics , are commending the U.S. Congress and President Obama for their recognition ... President of the American Innovation and Competitiveness Act (AICA). , The language of ...
(Date:1/11/2017)... ... 11, 2017 , ... While the most acute effects of ... increasingly clear that the evolution and transmission dynamics of resistance gene dissemination is ... of clinical resistance, has vastly underestimated these reservoirs of resistance genes. , ...
(Date:1/11/2017)... , ... January 11, 2017 , ... ... make all the difference when navigating the challenges young businesses face. With the ... the extensive expertise and experience of Geoff DiMasi, Founder and Principal of interactive ...
(Date:1/11/2017)... ... January 11, 2017 , ... ... has joined its team. Bernhard Bartylla will lead European initiatives for APMT’s product ... to introduce ACOMP and ARGEN to European manufacturers and researchers. Bernhard brings significant ...
Breaking Biology Technology: