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:3/29/2017)... 29, 2017  higi, the health IT company that ... North America , today announced a Series B ... of EveryMove. The new investment and acquisition accelerates higi,s ... to transform population health activities through the collection and ... higi collects and secures data today on behalf ...
(Date:3/27/2017)... 2017  Catholic Health Services (CHS) has been ... (HIMSS) Analytics for achieving Stage 6 on the ... In addition, CHS previously earned a place in ... electronic medical record (EMR). "HIMSS Analytics ... EMR usage in an outpatient setting.  This recognition ...
(Date:3/24/2017)... Research and Markets has announced the addition of the ... Forecast to 2025" report to their offering. ... The Global Biometric Vehicle Access System ... over the next decade to reach approximately $1,580 million by 2025. ... forecasts for all the given segments on global as well as ...
Breaking Biology News(10 mins):
(Date:10/12/2017)... ... 12, 2017 , ... DuPont Pioneer and recently formed CasZyme, ... into a multiyear collaboration to identify and characterize novel CRISPR-Cas nucleases. The goal ... editing across all applications. , Under the terms of the agreement, Pioneer will ...
(Date:10/12/2017)... CA (PRWEB) , ... October ... ... (https://www.onramp.bio/ ) has launched Rosalind™, the first-ever genomics analysis platform specifically designed ... bioinformatics complexity. Named in honor of pioneering researcher Rosalind Franklin, who made ...
(Date:10/11/2017)... ... October 11, 2017 , ... ComplianceOnline’s Medical Device Summit is back ... 8th June 2018 in San Francisco, CA. The Summit brings together current and former ... CEOs, board directors and government officials from around the world to address key issues ...
(Date:10/11/2017)... , ... October 11, 2017 , ... Disappearing forests and ... lives of over 5.5 million people each year. Especially those living in larger cities ... Treepex - based in one of the most pollution-affected countries globally - decided to ...
Breaking Biology Technology: