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.
Make way for the mini flying machines
21.03.2018 | American Chemical Society
New 4-D printer could reshape the world we live in
21.03.2018 | American Chemical Society
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.
In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...
Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...
19.03.2018 | Event News
16.03.2018 | Event News
13.03.2018 | Event News
21.03.2018 | Physics and Astronomy
21.03.2018 | Materials Sciences
21.03.2018 | Life Sciences