Auditory neuropathy (AN) is a type of deafness characterized by absence of auditory brainstem responses despite robust otoacoustic emissions, suggesting that outer hair cells are intact while inner hair cells (IHCs) and/or afferen neurons are dysfunctional. The AN phenotype can be either hereditary or acquired. Prematurity is an important risk factor for acquired AN in human populations, and, in animal models, AN can also be produced by the ototoxic anti-cancer drug, carboplatin. Two recent observations from our laboratory suggest that thiamine deficiency may be a key to the genesis of selective IHC loss, and therefore to acquired AN, in both prematurity and carboplatin therapy: 1) there is a striking prevalence of selective IHC loss in premature infants, and 2) IHCs have a unique vulnerability to thiamine (vitamin B1) deficiency in a mouse lacking a key transporter gene. Using animal models and human temporal bones obtained at autopsy, we will test the following hypotheses: 1) that the unique vulnerability of neonatal IHCs arises because of late-onset of expression of the key thiamine transporter genes in the inner ear, 2) that thiamine deficiency during late gestation or early post-natal life can cause selective IHC loss in otherwise healthy mice, and 3) that thiamine supplementation during carboplatin treatment can rescue the IHC loss that produces AN. If these novel hypothesized links are validated, simple therapies based on thiamine supplementation could be safe and effective in reducing the prevalence of hearing loss among infants in the neonatal intensive care unit and among children or adults undergoing anti-cancer therapies with platinum-based drugs.

Public Health Relevance

Recent work has generated the novel hypothesis that a particular type of acquired deafness known as auditory neuropathy arises from the special dependence of one type of inner ear sensory cell, the inner hair cell, on thiamine, also known as vitamin B1. If the experiments proposed here to test this hypothesis are successful, the results should lead to a clinical trial of the efficacy of thiamine supplementation in the prevention of auditory neuropathy among newborns.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DC012599-02
Application #
8484819
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Cyr, Janet
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$194,156
Indirect Cost
$75,406
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114