Discovery points to one possible path to novel drug development for cancer, AIDS, some inflammation
Using a new approach, Mayo Clinic researchers have successfully "taught" an RNA molecule inside a living cell to work as a decoy to divert the actions of the protein NF-kappaB, which scientists believe promotes disease development. The findings are published in the current issue of Proceedings of the National Academy of Sciences.
Although it also plays helpful roles in the body, NF-kappaB (pronounced "en-ef-kappa-bee):
The good news is that once it is diverted by the RNA decoys, NF-kappaB should no longer be available to play its negative role in the chain of molecular events that leads to disease. Mayos experimental findings suggest that this could be a new and effective strategy for developing drugs capable of halting the disease process.
In the paper, L. James Maher, III, Ph.D., and Laura Cassiday, Ph.D., Mayo Clinic Department of Biochemistry and Molecular Biology, describe their success with yeast cells and decoy RNA. Under natural conditions in the body, RNA delivers DNAs plans to cells, which make all the worker proteins to carry out DNAs executive orders. Drs. Maher and Cassiday have used the RNA/NF-kappaB pairs to divert the NF-kappaB protein. This diversion ensures that the disease-directing capability of NF-kappaB never reaches the DNA.
"Were trying to develop a somewhat nontraditional drug that is made out of RNA -- which is similar to DNA -- because it has some advantages over other drugs," says Dr. Maher, a molecular biologist. The experiment was performed in his laboratory. "One advantage is that it can be produced by the bodys own cells using a gene-therapy approach in which cells are given the gene for this decoy RNA. But this is a long way off. Whats exciting for us at this point are two discoveries: One is that the small RNAs that we are studying can be taught to do new and exciting things inside living cells. The other is that we have found a new way to use yeast cells as a powerful test system for helping us find the RNAs that are most likely to work in mammalian cells."
"Theoretically, if we want to stop any of these diseases in which NF-kappaB is known to be involved -- cancers, AIDS, some inflammatory diseases -- wed like to stop the action of this protein; that would be a long-term goal," adds Dr. Cassiday, who is a post-doctoral fellow at Mayo Graduate School. "Our short-term goal is to learn the capabilities of these small, folded RNAs."
The Experiment: How It Works, Where It Leads
Step 1: Test tube experiments
In Dr. Mahers lab, researchers used a novel approach to finding the right decoy RNAs. Lori Lebruska, Ph.D., a graduate of Mayo Graduate School, took a random collection of one hundred thousand billion (thats one followed by 14 zeroes) small RNAs. She then mixed the RNAs with NF-kappaB protein and captured the "smartest" RNAs on a filter. After many repeated capture cycles, the RNAs that stuck best to NF-kappaB were the most likely to be competent decoys.
Step 2: Testing the RNA decoy in a living cell.
Drs. Maher and Cassiday had to see if the decoy RNA could bind NF-kappaB not just in a test tube but in the chaos of a cell.
"Its a whole different ball game in the cell, because there are thousands of other proteins that the RNA might bind to," says Dr. Cassiday. "These proteins could distract it from what we want it to do: find and bind to NF-kappaB. We werent sure the RNA was specific enough to target NF-kappaB under these conditions. Also, there are all sorts of enzymes that degrade RNA within a cell. We werent sure the RNA would be stable enough to survive and do its job. These were all considerations that needed to be resolved in our cellular experiments."
To test the RNA decoys ability to adapt to life inside cells, the researchers chose yeast, which is very similar to human cells, as a model organism.
"The rules change inside the cell," says Dr. Maher. "The real question becomes how can we send the RNA molecules back to school to adapt to these new cellular rules when all they previously knew how to do was succeed with test-tube rules?"
After simultaneously screening thousands of RNA variations in yeast, Drs. Cassiday and Maher found one RNA that had learned to do it all. Dr. Maher notes that by increasing the amount of this molecule, bigger and bigger decoy effects emerge, allowing for significant inhibition of NF-kappaBs disease capabilities.
The next step for the Mayo research team is to adapt this RNA decoy to life in mammalian cells to see if it can "learn" the additional rules necessary to survive and foil NF-kappaB in its natural setting. If it does, it might one day be a candidate for a new kind of drug therapy.
More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn
How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.
We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
19.01.2018 | Materials Sciences
19.01.2018 | Health and Medicine
19.01.2018 | Physics and Astronomy