Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers discover molecular trigger of inflammatory bowel disease

17.02.2015

Cells lining the intestinal tract form a critical barrier, protecting our bodies from the billions of bacteria living in the gut. Breaches in this barrier are driven largely by a single signaling molecule called tumor necrosis factor (TNF), elevated amounts of which are associated with inflammatory bowel diseases like Crohn's disease and ulcerative colitis.

Drugs targeting TNF have become an effective treatment against these illnesses, but despite its clinical importance, it is still not clear what triggers an uptick in TNF levels in the gut, or how that event leads to the onset of disease.


Image of a zebrafish in which the entire intestine is highlighted in red and the expression of the TNF molecule is highlighted in green. Duke researchers have discovered that a gene called uhrf1 acts like a kind of molecular handbrake on TNF, keeping it from setting off the series of pro-inflammatory and immune signals that drive inflammatory bowel diseases.

Credit: Lindsay Marjoram, Duke University

Duke researchers now have discovered that a gene called uhrf1 acts like a kind of molecular handbrake on TNF. In the absence of uhrf1, TNF rolls out a series of pro-inflammatory and immune signals that inflame and damage the digestive tract.

"Our findings provide a new take on how inflammatory bowel diseases can emerge and develop," said Michel Bagnat, Ph.D., an assistant professor of cell biology at Duke University School of Medicine. "We already knew that genetic susceptibility could play a part, but we've found that it is not just the immune genes themselves, but also the regulation of those genes (through epigenetics), that can cause problems."

The findings appear the week of February 16 in the Proceedings of the National Academy of Sciences.

Inflammatory bowel diseases (IBD) are a group of chronic disorders of the gastrointestinal tract that affect over 1.6 million Americans. Though the origins of these diseases are unclear, recent research has implicated a number of factors, including genetic variation, intestinal microbes, overactive immunity, and environmental exposures.

Bagnat decided to use an experimental approach called forward genetics to uncover new causes of IBD. First, his postdoctoral fellow Lindsay Marjoram used chemicals to induce mutations in their model organism of choice, the zebrafish. Because these small aquarium fish are transparent as embryos, she could easily visualize any defects in the gut as they developed.

After screening hundreds of mutants, Marjoram found several strains that displayed marked gut defects, including a thinner protective barrier and chunks of floating cellular debris.

Next, the researchers decided to narrow down their results to only the mutants involved in inflammation. Because TNF activity is a hallmark of inflammation, they created a "reporter" zebrafish that lit up green wherever the TNF gene was "turned on" in the organism. The researchers then bred the TNF reporter fish to the mutants from their initial screen to see if any of the mutated genes affected the expression of this important pro-inflammatory molecule.

The experiment yielded two big surprises. First, they found that TNF, originally thought to be produced mostly by immune cells, was also being made by the epithelial cells that line the gut. Second, they discovered that one of the mutants actually pumped up the levels of TNF being produced in the digestive tract.

After a bit more genetic investigation, the researchers found that the gene responsible was uhrf1, which is involved in an epigenetic process known as DNA methylation. Whether a particular gene is turned "off" or "on" in a given cell is determined by the presence or absence of specific chemical tags or methyl groups -- methylation -- attached to the DNA.

Uhrf1 normally acts to turn off genes that produce TNF, but when that repression is lost, those genes get turned on and TNF is manufactured and released. "You can think about it in terms of a car parked in a driveway. If you get rid of the handbrake, the car is going to start rolling," Bagnat said.

In collaboration with Mary Goll of Memorial Sloan-Kettering Cancer Center, the researchers demonstrated that loss of uhrf1 did indeed remove methylation from the TNF gene.

Next, Bagnat turned to his Duke colleague John Rawls to explore whether the guts of the zebrafish had to be exposed to bacteria that set off TNF's pro-inflammatory activities. When they raised the zebrafish mutants in a germ-free environment, TNF was still activated, though to a lesser extent. The results suggested that losing uhrf1's brakes was enough to head TNF on a course for destruction, even without that extra push from intestinal microbes.

Now the researchers are trying to translate their findings to higher organisms like humans by looking for similar methylation defects in patients with IBD. Ultimately, the defects they find could provide targets for new diagnostics or therapeutics for the disease.

The research was supported by a National Institutes of Health New Innovator Award (DP2 3034656), a Bill & Melinda Gates Foundation Grand Challenges Exploration grant (OPP1108132), a Duke Multidisciplinary Fellowship in Pediatric Lung Disease (5T32HL098099-02), an F32 NRSA (DK098885-01A1), and a grant from the March of Dimes Foundation (5-FY12-93).

CITATION: "Epigenetic control of intestinal barrier function and inflammation in zebrafish," Lindsay Marjoram, Ashley Alvers, M. Elizabeth Deerhake, Jennifer Bagwell, Jamie Mankiewicz, Jordan Cocchiaro, Rebecca W. Beerman, Jason Willer, Kaelyn Sumigray, Nicholas Katsanis, David M. Tobin, John F. Rawls, Mary Goll, Michel Bagnat. PNAS, Feb. 16, 2015. DOI: 10.1073/pnas.1424089112

Media Contact

Karl Bates
karl.bates@duke.edu
919-681-8054

 @DukeU

http://www.duke.edu 

Karl Bates | EurekAlert!

More articles from Health and Medicine:

nachricht Why might reading make myopic?
18.07.2018 | Universitätsklinikum Tübingen

nachricht Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Machine-learning predicted a superhard and high-energy-density tungsten nitride

18.07.2018 | Materials Sciences

NYSCF researchers develop novel bioengineering technique for personalized bone grafts

18.07.2018 | Life Sciences

Why might reading make myopic?

18.07.2018 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>