Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Pig model of cystic fibrosis improves understanding of disease

The new model provides insight on how the CF gene mutation causes disease, and may provide a useful system to test therapies targeting the effects of the mutation

It's been more than 20 years since scientists first discovered the gene that causes cystic fibrosis (CF), yet questions about how the mutated gene causes disease remain unanswered.

Using a newly created pig model that genetically replicates the most common form of cystic fibrosis, University of Iowa researchers have now shown that the CF protein is "misprocessed" in the pigs and does not end up in the correct cellular location. This glitch leads to disease symptoms, including gastrointestinal abnormalities and lung disease in the pigs, which mimic CF in humans. The findings are published in the March 16 issue of the journal Science Translational Medicine.

The findings match earlier laboratory experiments that suggested the gene mutation disrupts the process whereby the CF protein is folded into its correct shape and shipped to the membranes of cells that line the airways and other organs.

When it is correctly located at the cell membrane, this protein -- called cystic fibrosis transmembrane conductance regulator (CFTR) -- forms a channel to allow chloride ions to move in and out of cells. This ion movement is a critical component of the system that maintains salt and water balance across cell membranes in the lung as well as other organs and supports normal membrane function including eradicating bacteria from cell surfaces.

The new study shows that in pigs, the CFTR protein behaves the same way in a living animal as it does in experimental cell systems, suggesting that these experimental systems are useful for learning about the CFTR protein's properties. The cell systems and the new pig model may also be helpful in testing therapies designed to increase the amount of protein that gets to the cell membrane, or boost the activity of the protein that is located at the membrane.

"Instead of just trying to treat the symptoms of CF, current research is moving toward therapies that target mutations in the CFTR gene," said David Stoltz, M.D., Ph.D., UI assistant professor of internal medicine and senior study author. "For example, there already are drugs known as "correctors" being tested. These drugs help CFTR move from inside the cell to its correct location on the cell surface.

"The pig model could help us develop and test more corrector drugs, and it will also help us better understand why the protein is misprocessed in the first place," Stoltz added. "If we understand what is going wrong, we may be able to develop new therapies that can target the problem and allow more of the CFTR to make it to the cell surface, which may alleviate the disease symptoms."

In 2008, the UI team and colleagues at University of Missouri created pigs that were missing the CFTR protein. These animals developed CF disease symptoms that closely mimicked the human disease. In the new pig model, the animals have two copies of the CFTR gene containing the most common CF-causing mutation, which is known as the delta F508 mutation. These pigs also develop CF symptoms similar to the human disease. In particular, the CF pigs are born with gastrointestinal disease and develop lung disease over time.

By studying the protein in the pigs, the researchers were able to show that most of the CFTR protein is misprocessed and gets degraded, but a small amount of the protein does get to the cell membrane where it is able to form active chloride channels. However, the level of activity is only about 6 percent of the activity found in normal pigs with fully functional CFTR channels. The study shows that this small amount of CFTR activity is not sufficient to prevent CF disease in the pigs.

CF is a recessive disease, meaning a person with one mutated copy and one good copy of the CFTR gene is a "carrier" but does not have CF. This suggests that 50 percent of normal CFTR activity is sufficient for health. The question has always been, 'Is there a minimal amount of active CFTR that would be enough to protect people from the disease symptoms?'

"We know that people with 50 percent CFTR function have no disease, and now we know that 6 percent of full activity is not enough to prevent disease in the pigs," Stoltz said. "We still don't know how much CFTR is enough to prevent the disease, but this model animal could give us a way to investigate."

In addition to Stoltz, the UI research team included senior author Michael Welsh, M.D., UI professor of internal medicine and molecular physiology and biophysics and a Howard Hughes Medical Institute investigator, and co-first authors, Lynda Ostedgaard, Ph.D.; David Meyerholz, D.V.M., Ph.D.; and Jeng-Haur Chen, Ph.D.

This work was a collaboration between UI scientists and scientists at the University of Missouri including Dr. Randall Prather and members of his research team.

Researchers from the UI Departments of Internal Medicine, Pathology, Surgery and Pediatrics were also part of the team.

The study was funded in part by grants from the National Institutes of Health and the Cystic Fibrosis Foundation.

Jennifer Brown | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Here comes the long-sought-after iron-munching microbe
25.10.2016 | Max-Planck-Institut für marine Mikrobiologie

nachricht Novel method to benchmark and improve the performance of protein measumeasurement techniques
25.10.2016 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

First-time reconstruction of infectious bat influenza viruses

25.10.2016 | Life Sciences

Novel method to benchmark and improve the performance of protein measumeasurement techniques

25.10.2016 | Life Sciences

Amazon rain helps make more rain

25.10.2016 | Life Sciences

More VideoLinks >>>