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New UVa research could help restore hearing loss

Treatments for hearing loss have eluded researchers and clinicians for decades. Now, researchers at the University of Virginia have discovered how hearing cells repair themselves after being damaged. Their findings, published June 9 in the journal eLife, could help researchers discover new ways to restore hearing loss associated with stress and aging.

The field studying hearing loss has historically emphasized regenerating auditory “hair cells,” cells in the inner ear that detect sound, after they die. But researchers are still many years away from regrowing the cells at a level sufficient to restore hearing, according to Jung-Bum Shin, associate professor of neuroscience at UVa and one of the authors of the study.

“We’re saying, if you can’t replace it, why not try to repair it?” Shin told The Daily Progress. “There has been very little effort into learning how to repair these hair cells. That’s where we see our opportunity as a research group.”

Humans are born with around 16,000 hair cells in the inner ear. The cells are covered in stereocilia, “mechanical antennas for sound detection,” Shin said. Stereocilia are sensitive by design, as they must be able to detect vibrations caused by sound. But that also means they can easily break if overstimulated with too loud of a noise.

Stereocilia naturally repair themselves throughout our lives, Shin said. That’s likely why you can’t hear as well right after a loud concert but can hear just fine after more time has passed. That’s also likely why most people have normal hearing until age 60.

But as we grow older, the repair process can become “exhausted” and the hair cells can die instead of repairing themselves, Shin said. That process is sped up by repeated exposure to loud noise, genetic predisposition and certain pharmaceutical drugs such as cisplatin, a chemotherapy drug used to target many types of cancer.

Although there are likely multiple mechanisms stereocilia use to repair themselves, Shin and his team have discovered how one works. That understanding may eventually lead to treatments to facilitate repair and restore lost hearing.

When stereocilia are damaged, such as by a loud noise, microscopic lesions appear in the fibers. Shin’s group identified a protein called XIRP2 which detects the lesion, migrates to the broken site and facilitates repair.

“Imagine a rope, and let’s say the rope is under tension, it’s pulled from both sides,” Shin said. “And then you go in with a knife and start cutting at one side, then the rope starts fraying. You can now imagine that the remaining fibers of that rope are now under increased tension.”

Similarly, when lesions occur in stereocilia, XIRP2 has the ability to sense the change in tension of the remaining fibers and diffuse to the broken site, repairing the cell.

Although the study’s focus on hearing cells was specialized, the composition of those cells is anything but. Hearing cells are made up of actin filaments, protein filaments that are the “backbone” of many cells in the body. That means repair in other cells, such as in heart tissue, may function similarly to the one in auditory cells described in Shin’s work.

A group at the University of Chicago recently used a computational model to study cracked actin filaments and a certain family of proteins, LIM domains. Their findings, which are currently being peer reviewed, show that enough stress on the actin filaments exposes previously hidden binding sites. Proteins can then travel to those sites to begin repairing the cell.

“What the simulation can do, which direct experimentation can’t do right now, is provide more molecular specificity as to why this happens,” Gregory Voth, one of the authors of the study, told The Daily Progress. “Most pharmaceuticals are small molecules. If you know the molecular structure of something and what it’s doing, you can design a molecule that can help come up with ways to fix, say, hearing loss.”

While the UVa group is studying the process at a subcellular level, “we’re seeing something at the atomistic level,” Vilmos Zsolnay, the lead author of the study, told The Daily Progress. “And you can connect those two in terms of what you think is going on.”

“This paper was a great validation of our suspicions,” Shin said. A next step for the UVa research group may be to model the structure of XIRP2 and integrate it into the actin model to observe, on a molecular level, how the protein binds to cracked actin folds.

Since XIRP2 is in the very family of proteins his group modeled, Zsolnay said that would be “pretty straightforward” to accomplish.

A cure for hearing loss is still more than a few years away, Shin said. In fact, it is very difficult to manipulate an individual protein such as XIRP2. However, the group is now looking for a “master switch,” a gene that controls a number of transcription factors, including the repair protein.

“Once we turn it on, we can turn on a whole slew of repair mechanisms,” Shin said. Once they identify the “switch” to initiate repair, researchers can identify molecules and drugs to target the repair mechanisms and fix the damaged hearing cells.

Shin’s group isn’t the only one working towards the eventual goal of restoring hearing loss. A research group at Harvard Medical School published a study in April focusing on the regenerative model, an approach that has eluded the field for decades, which seeks to regrow auditory hair cells that have died.

The Harvard group showed that a cocktail of drug-like molecules were successfully able to regrow auditory hair cells in mature mice over a one year period, according to Zeng-Yi Chen, one of the authors of the study. In the next five years, the field may accomplish robust hair cell regeneration in animal models, moving one step closer to restoring hearing loss in humans.

Repair and regeneration are on a “continuum” of treatments for hearing loss, Chen told The Daily Progress. When a hair cell is damaged by noise, the cell might remain for decades in the same spot. If the damage isn’t so severe, the cell can be repaired. But when cells die and there aren’t enough to hear, that’s when treatment would turn to regeneration, although it is still many years away.

“Hearing loss is one major medical field without any real treatment,” Chen said. “I think we are at the very historic junction where a new type of therapy will be forthcoming.”

Source: www.dailyprogress.com

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