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:1/27/2016)... Jan. 27, 2016  Rite Track, Inc. a leading ... West Chester, Ohio announced today the ... staff, based in Austin, Texas , ... to provide modifications, installations and technical support offerings for ... of PLUS, commented, "PLUS has provided world class service ...
(Date:1/21/2016)... , January 21, 2016 ... to a new market research report "Emotion Detection and ... Others), Software Tools (Facial Expression, Voice Recognition and ... - Global forecast to 2020", published by MarketsandMarkets, ... expected to reach USD 22.65 Billion by 2020, ...
(Date:1/15/2016)... SAN JUAN, Puerto Rico , Jan. 15, 2016 ... forcing companies big and small to find new ways ... data driven culture. iOS and ... their device based on biometrics, transforming it into a ... can request that users swipe their fingerprint on their ...
Breaking Biology News(10 mins):
(Date:2/9/2016)... , ... February 09, 2016 , ... Tunnell Consulting, Inc. ... Based in Paris, he will focus on acquiring new accounts and work closely with ... , “Fred brings to our European clients more than 15 years of ...
(Date:2/9/2016)... NEW YORK , Feb. 9, 2016 ... market analyzes the current and future prospects of the ... of this report include companies engaged in the manufacture ... comprises an executive summary with a market snapshot providing ... the scope of this report. This section also provides ...
(Date:2/8/2016)... , Feb. 8, 2016 /PRNewswire/ - BIOREM Inc. (TSXV: ... the top ten finalists for clean technology companies in the ... the top 10 companies listed on the TSX Venture Exchange, ... & gas, clean technology & life sciences, diversified ... equal weighting given to return on investment, market cap growth, ...
(Date:2/8/2016)... ... February 08, 2016 , ... Thomas J. Todorow has joined ... President for Corporate Services and the Chief Financial Officer at The Children’s Hospital ... Treasury, Managed Care Contracting, Supply Chain, and Investments. , Prior to joining CHOP ...
Breaking Biology Technology: