Findings suggest several FDA-approved drugs, such as a common diabetes medication and anesthetics, could protect from noise-related hearing loss.


Date:
September 29, 2021
Source:
University of Maryland School of Medicine
Summary:
A team led by researchers has published an online interactive
atlas representing the changes in the levels of RNA made in the
different cell types of ears of mice, after damage due to loud
noise. From this analysis, the research teams identified a handful
of drug candidates that may be able to prevent or treat the damage,
and ultimately preserve hearing.



FULL STORY ==========================================================================
A growing number of people are suffering from hearing loss due to exposure
to loud noises from heavy machinery, concerts, or explosions. As a result, scientists have been working to understand the mechanism behind how the
damage to hearing actually occurs.


==========================================================================
Now, a team led by researchers at the University of Maryland School of
Medicine (UMSOM) has published an online interactive atlas representing
the changes in the levels of RNA made in the different cell types of ears
of mice, after damage due to loud noise. These changes in RNA levels are
known as changes in "gene expression." Once they determined the larger
trends in gene expression following the damage, the UMSOM scientists
then searched a database of FDA-approved drugs to find those that are
known to produce opposite patterns of those caused by the noise.

From this analysis, the research teams identified a handful of drug
candidates that may be able to prevent or treat the damage, and ultimately preserve hearing.

Their analysis was published in Cell Reports on September 28.

"As an otolaryngologist surgeon-scientist, I see patients with hearing
loss due to age or noise damage, and I want to be able to help prevent
or even reverse the damage to their hearing," said study leader Ronna
Hertzano, MD, PhD, Professor of Otorhinolaryngology-Head & Neck Surgery, Anatomy and Neurobiology at UMSOM and Affiliate Member of UMSOM's
Institute for Genome Sciences. "Our extended analysis gives us very
specific avenues to follow up on in future studies, as well as provides
an encyclopedia that other researchers can use as a resource to study
hearing loss." The team added their newest data on noise-induced hearing
loss to gEAR -- Gene Expression Analysis Resource -- a tool developed
by her laboratory that allows researchers not trained in informatics to
browse gene expression data (published earlier this summer).



==========================================================================
Dr. Hertzano explained that the inner ear resembles the shell of a
snail, with separate fluid compartments and sensory cells along its
entire length. The ear functions like a battery with a gradient of ions
between the fluid compartments that is generated by the side wall of the
shell by adding in potassium. The sensory cells detect sound and then communicate with the neurons that interact with the brain to interpret
the signal. The sensory cells are surrounded by support cells. The inner
ear also has resident immune cells to protect it from infection.

Research Supervisor Beatrice Milon, PhD, in Dr. Hertzano's laboratory
initially did an analysis on the sensory cells and the support cells of
the ear in mice.

She collected data on the changes in gene expression from before and
after noise damage. After making their study known to other researchers in their field, the team heard from scientists at Decibel Therapeutics (led
by Joe Burns, PhD) and the Karolinska Institute (led by Barbara Canlon,
PhD), who had the gene expression data from the inner ear's neurons,
side wall and immune cells from before and after noise damage. The teams
then combined the datasets and performed their analysis.

The bioinformatic analyses were led by Eldad Shulman, MA, MS, from the
lab of Ran Elkon, PhD, Tel Aviv University, a bioinformatics expert
that has been working collaboratively with Dr. Hertzano now for over
two decades. Together, they leverage advanced computational techniques
and combine them with biological insights to analyze and interpret data, providing impactful insights to the hearing research field.

Dr. Hertzano says it was so important that they looked at a cell specific level, rather than looking at the entire ear because they found that
most of the gene expression changes were specific to only one or two
cell types.

"We expected the subset of neurons typically sensitive to noise and aging,
to have "bad" changes in genes, so that we could counter them with drugs,
but there was no such thing," said Dr. Hertzano. "On the contrary, we
found that the subset of neurons that are resistant to noise trauma,
turn on a program that protects them while the very sensitive neurons
had little change in gene expression. We are currently looking into
approaches to induce the protective changes in the noise-sensitive neurons
to prevent their loss from noise and aging." In another example, the researchers found that only one out of the four types of immune cells
detected showed major differences in gene expression.



========================================================================== Additionally, immune-related genes were turned up in all cell types of
the inner ear after noise damage with many of them controlled by two
key regulators.

The research team took the overall gene expression trends and plugged them
into DrugCentral, a database of known molecular responses to FDA-approved drugs, specifically searching for changes that would be opposite of those happening in the noise-damaged cells. They identified the diabetes drug metformin as a potential candidate, as well as some inhaled anesthetic medications used in surgeries and other medications.

"Hearing aids and cochlear implants are used to alleviate hearing loss, however, there are no therapies available to prevent or treat hearing
loss," said E. Albert Reece, MD, PhD, MBA, Executive Vice President
for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor, and Dean, UMSOM. "The studies that follow
up on these findings may eventually lead to medications to prevent
occupational noise-induced hearing loss, for example in factory workers,
and to changes in standardizing anesthesia protocols for ear surgery, particularly in hearing preservation procedures." This work was funded
by the Eunice Kennedy Shriver National Institute of Child Health and
Human Development (R01DC013817, R01DC03544), the Department of Defense Congressionally Directed Medical Research Program (MR130240, RH200052),
the Carolyn Frenkil Foundation, the Hearing Restoration Project of the
Hearing Health Foundation, the Swedish Medical Research Council and Ho"rselforskningsfonden, the Karolinska Institutet, Tysta Skolan and
Office of the Assistant Secretary of Defense for Health Affairs through
the Neurosensory and Rehabilitation (W81XWH-16-1-0032), the European
Union's Horizon 2020 research and innovation programme (722046, 848261),
the United States -- Israel Binational Science Foundation (2017218),
the Edmond J. Safra Center for Bioinformatics at Tel Aviv University,
Teva Pharmaceutical Industries Ltd, and the Israeli National Forum for BioInnovators.

========================================================================== Story Source: Materials provided by
University_of_Maryland_School_of_Medicine. Original written by Vanessa
McMains. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Beatrice Milon, Eldad D. Shulman, Kathy S. So, Christopher
R. Cederroth,
Erika L. Lipford, Michal Sperber, Jonathan B. Sellon, Heela Sarlus,
Gabriela Pregernig, Benjamin Shuster, Yang Song, Sunayana Mitra,
Joshua Orvis, Zachary Margulies, Yoko Ogawa, Christopher Shults,
Didier A.

Depireux, Adam T. Palermo, Barbara Canlon, Joe Burns, Ran Elkon,
Ronna Hertzano. A cell-type-specific atlas of the inner ear
transcriptional response to acoustic trauma. Cell Reports, 2021;
36 (13): 109758 DOI: 10.1016/j.celrep.2021.109758 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210929124349.htm

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