Hearing loss and vertigo are serious health problems that currently affect millions of Americans. Normal sensory function of the inner ear relies on mechanoreceptive hair cells, which convert sound vibrations and head movements into electrical signals that are conveyed to the brain. Hair cells can be injured or lost as a result of noise exposure, ototoxic medications, inner ear infections, or as part of normal aging. The inner ears of mammals (including humans) are unable to replace these cells, and the death of hair cells is the most common cause of sensorineural deafness. In contrast, the ears of nonmammalian vertebrates can quickly regenerate hair cells after injury, and it is of great interest to understand the cellular basis of this regenerative process. This proposal focuses on a novel and relatively unexplored aspect of regenerative biology. Prior research has shown that macrophages - the primary effector cells of the innate immune system - are critically involved in repair and regeneration of many types of somatic tissues. The cochlea and vestibular organs contain large numbers of macrophages, but the function of those cells within the ear is completely unknown. Our prior work has suggested that macrophages may help promote hair cell regeneration, but a direct demonstration has remained elusive. The proposed studies will address these long-standing issues, and will make use of newly-developed methods for selective elimination of hair cells and/or macrophages from the mature ear, both in vitro and in vivo. The outcome of the proposed experiments will indicate whether macrophages play a stimulatory or suppressive role in regeneration. Notably, knowledge acquired from this work will also extend beyond the realm of regenerative medicine. Many inner ear pathologies respond to immunosuppressive therapies. The cellular basis of such treatments is unknown, but these observations point to direct effects of inflammatory cells on the sensory structures of the ear. As such, completion of these projects will resolve many outstanding questions regarding the contribution of otic macrophages to sensory repair and will also provide new insights into the nature of the cellular dialogue between the innate immune system and the inner ear.

Public Health Relevance

Hearing loss and vertigo are serious health problems that affect millions of Americans. This proposal focuses on identifying the role of macrophages and the innate immune system in the processes of repair and regeneration in the mature inner ear. Such knowledge could suggest new mechanisms for restoring sensory function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC006283-08A1
Application #
8235172
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2003-07-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$323,000
Indirect Cost
$110,500
Name
Washington University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Tong, Ling; Strong, Melissa K; Kaur, Tejbeer et al. (2015) Selective deletion of cochlear hair cells causes rapid age-dependent changes in spiral ganglion and cochlear nucleus neurons. J Neurosci 35:7878-91
Kaur, Tejbeer; Zamani, Darius; Tong, Ling et al. (2015) Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion. J Neurosci 35:15050-61
Kaur, Tejbeer; Hirose, Keiko; Rubel, Edwin W et al. (2015) Macrophage recruitment and epithelial repair following hair cell injury in the mouse utricle. Front Cell Neurosci 9:150
Ku, Yuan-Chieh; Renaud, Nicole A; Veile, Rose A et al. (2014) The transcriptome of utricle hair cell regeneration in the avian inner ear. J Neurosci 34:3523-35
Slattery, Eric L; Oshima, Kazuo; Heller, Stefan et al. (2014) Cisplatin exposure damages resident stem cells of the mammalian inner ear. Dev Dyn 243:1328-37
Huh, Sung-Ho; Jones, Jennifer; Warchol, Mark E et al. (2012) Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. PLoS Biol 10:e1001231
Warchol, Mark E; Schwendener, Reto A; Hirose, Keiko (2012) Depletion of resident macrophages does not alter sensory regeneration in the avian cochlea. PLoS One 7:e51574
Warchol, Mark E (2011) Sensory regeneration in the vertebrate inner ear: differences at the levels of cells and species. Hear Res 273:72-9
Alvarado, David M; Hawkins, R David; Bashiardes, Stavros et al. (2011) An RNA interference-based screen of transcription factor genes identifies pathways necessary for sensory regeneration in the avian inner ear. J Neurosci 31:4535-43
Warchol, Mark E (2010) Cellular mechanisms of aminoglycoside ototoxicity. Curr Opin Otolaryngol Head Neck Surg 18:454-8

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