Elevated Cochlear Adenosine Causes Hearing Loss Via Adora2B Signaling

<p>Over 538 million people in the world have been diagnosed with hearing loss (HL). Current treatments for the most common type of HL, sensorineural HL, are limited to hearing aids and cochlear implants with no FDA-drugs available. The hearing process demands an abundance of ATP and HL is often attributed to a disruption in this metabolic energy currency. Patients who lack adenosine deaminase (ADA), the enzyme that irreversibly metabolizes adenosine, have high levels of adenosine that yield severe health problems, including HL; however, the pathogenic mechanisms behind HL and adenosine remain elusive. Our lab has found a HL phenotype in Ada-deficient mice (<em>Ada</em>^-/-) that parallels ADA-deficient humans. We characterized shifts in both DPOAE and ABR thresholds in <em>Ada</em>^-/- mice with high adenosine levels. Moreover, we found that these mice have an overall lowered firing capacity of both peripheral and cochlear nucleus and slow latency transmission between structures. We also observed nerve fiber density loss and aberrant myelin compaction. More importantly, we found that treatment of FDA-approved drug, polyethylene glycol-ADA (PEG-ADA), lowered cochlear adenosine levels and improved functional and structural phenotypes of <em>Ada^-/-</em> mice. In addition to continuous treatment of PEG-ADA in <em>Ada</em>^-/- mice, we also rescued these phenotypes in mice with HL after adenosine accumulation for two weeks. Together, these results provide fundamental evidence that elevated cochlear adenosine causes hearing loss via perturbations of myelin structures.</p> <p>Interestingly, out of all four adenosine receptors, adenosine a2b (ADORA2B) was found to have the highest mRNA expression in untreated <em>Ada</em>^-/- cochlea. We observed that genetically and pharmacologically ablating ADORA2B in the <em>Ada</em>^-/- mice attenuated hearing deficiencies and rescued nerve fiber density and myelin compaction of cochlear nerve. With these findings, we reveal that elevated adenosine-mediated hearing loss is dependent on ADORA2B signaling that leads to overall hearing sensitivity decline.</p> <p>Extending from our <em>Ada</em>^-/- mice, we used aged mice as an additional SNHL model. Aging organs have been associated with hypoxia and, consequently, increased adenosine levels. Indeed, we found that aged <em>Adora2b</em>^-/- rescued hearing sensitivity. Moreover, we used a therapeutic approach for both models to further validate the role of ADORA2B by using a specific- ADORA2B antagonist, PSB1115. PSB1115-treated aging mice also have rescued hearing sensitivity. We also explored another disease model that our lab found to have elevated systemic adenosine with reported HL in the clinic: sickle-cell disease (SCD). We found that C57B6/J mice transplanted with SCD mice bone marrow (BM) have hearing loss; however, we found that <em>Adora2b</em>^-/- mice with SCD BM have attenuated hearing loss. Overall, our study supports the clinical and existing research on the relationship between adenosine signaling and hearing loss. Understanding this purinergic signaling establishes a strong foundation for molecular-based therapy in a very common disability.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2020

Authors dc:creator

• Manalo, Jeanne
• <p>0000-0001-7289-8102</p>

Contributors dc:contributor

• Yang Xia, MD, PhD
• Michael Beierlein, PhD
• John O'Brien, PhD

• adenosine
• adenosine a2b
• adora2b
• hearing loss
• sensorineural hearing loss
• aging
• presbycusis
• myelin protein zero
• Biochemistry
• Molecular and Cellular Neuroscience
• Molecular Biology
• Other Neuroscience and Neurobiology
• Systems Neuroscience

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1033

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2085