Promise for a treatment for acoustic trauma comes from the recent discovery by the applicants that there is a brief period following the injury when the inner ear itself may be capable of limiting or of self-repairing much of the damage. This rescue process can provide ~40dB reduction in permanent hearing loss and can be evoked by exposure to restraint stress (which releases glucocorticoids) and by administration of synthetic glucocorticoids (e.g. dexamethasone). Rescue from acoustic trauma is most effective when triggered days after the injury. The applicants have identified a corticosteroid-responsive transcription factor, PLZF (promyelocytic leukemia zinc finger protein), which is necessary to generate rescue from acoustic trauma. PLZF is elevated following restraint stress and corticosteroid administration, and mutant mice deficient in PLZF do not show rescue from acoustic trauma. The inability of PLZF-deficient mice to induce protection provides an opportunity to discover the underlying mechanism through which protection or repair of acoustic trauma is generated normally in the animal, and provides a pathway by which pharmacological therapies can be developed ultimately for human use.
The aims are to examine the influence of PLZF activation of leukocyte invasion and activation in the cochlea and to evaluate the consequences of those influences on acoustic trauma.
The specific aims are to: 1) determine which effect of acoustic trauma can be rescued via PLZF activation; 2) evaluate the effects of PLZF activation on cochlear leukocyte entry and macrophage activation state following acoustic trauma; and 3) determine the cell signals controlling the rescue response. Corticosteroids are, at present, one of the few available treatments for acute loss of hearing, and their mechanism(s) of action are not understood. While many promising potential targets of steroid activation have been analyzed in the ear, no compelling mechanism has yet been identified for its action. The discovery of a drug-responsive transcription factor that can induce repair of the ear following trauma provides a unique opportunity to develop pharmaceutical therapies to prevent life-long debilitating hearing loss. One can envision providing a drug after traumatic injury to the inner ea that could prevent or seriously reduce the amount of permanent hearing loss associated with the trauma. The therapeutic time window of a few days increases practicality of the therapy. The identification of a single, corticosteroid-responsive transcription factor that is essential to indce conditioning-mediated protection from acoustic trauma also offers a straightforward opportunity to identify specific molecular mechanisms that protect and repair the cochlea.

Public Health Relevance

The discovery that the cochlea can be rescued from acoustic trauma days after the initial assault suggests new approaches both for treating acoustic trauma and for understanding the underlying process that damages the ear. The proposed work will assess the general hypothesis that much of the damage from acoustic trauma arises from an inflammatory process following the injury and that the transcription factor, plzf, is key to rescuig the ear from permanent damage associated with that process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
4R01DC013138-04
Application #
8994727
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code