In the inner ear, the blood vessels that carry oxygen and nutrients to the hearing cells are carefully regulated so that fluids inside the blood vessel d not leak into the tissues of the inner ear. This separation between contents of the blood and contents of the inner ear is called the blood-perilymph barrier. This barrier regulates the immune system and controls the traffic of white blood cells from the blood stream into the organs. When the immune system is activated, white blood cells can leave the vessels, enter the target organ and eliminate harmful bacteria or unwanted cells, but at the same time, it can damage healthy tissues that were not the intended targets. Therefore, careful regulation of this barrier and the immune response are very important. Under certain conditions, when the barrier becomes leaky, fluids and solutes from the blood vessels mix with the inner ear fluids, and this mixing is believed to cause hearing loss, although this has not been proven. In our first series of experiments, we will determine how vessel permeability affects hearing. Our goal is to understand how disruption of this barrier influences hearing levels and how it can be repaired and hearing be retained. Our second series of studies will focus on the role of specific white blood cells that enter the cochlea during meningitis. Meningitis is a life-threatening infection of the spinal fluid and inner ear fluid where the blood-perilymph barrier and the blood-brain barrier are severely compromised. Meningitis is commonly associated with permanent hearing loss and sometimes with cochlear ossification, where new bone forms in the spaces that are normally fluid-filled. Cochlear ossification is a major concern because cochlear implants, which are our best tool for treating deafness, often cannot be placed when the space for the implant is filled with bone. We believe that the immune response to infection results in this new bone formation and contributes to hearing loss. Although the immune response is essential to eliminate the infection in meningitis, better control of the immune response may result in preserved hearing. If we could prevent the loss of hearing in patients with meningitis and prevent the formation of new bone in the cochlea after meningitis, it would greatly help the well being of people who are affected by this condition. The overall goals of this grant are to improve our understanding of how the immune system interacts with the inner ear environment, what parts of the immune system are beneficial, such as preventing or eliminating infections, and which of its functions might be harmful. Because many current therapies for hearing loss involve the use of medications that suppress the immune system, it is important to understand how the immune system works in the inner ear, to design better medications and improve the effectiveness of treatment for hearing loss.

Public Health Relevance

When the cochlea is injured or infected, immune cells exit the blood vessels and enter the fluid spaces of the cochlea. How normal vascular barriers exclude these cells from the inner ear during times of health and how the barriers break down to allow entry of immune cells when they are needed is not well known. We will explore how vessels control traffic of these cells, how this barrier breakdown affects hearing, and what steps lead to irreversible damage, such as scarring and new bone formation in the cochlea.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Watson, Bracie
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Washington University
Schools of Medicine
Saint Louis
United States
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Salt, Alec N; Hirose, Keiko (2018) Communication pathways to and from the inner ear and their contributions to drug delivery. Hear Res 362:25-37
Hirose, Keiko; Rutherford, Mark A; Warchol, Mark E (2017) Two cell populations participate in clearance of damaged hair cells from the sensory epithelia of the inner ear. Hear Res 352:70-81
Hirose, Keiko; Hartsock, Jared J; Johnson, Shane et al. (2014) Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph. J Assoc Res Otolaryngol 15:707-19
Hirose, Keiko; Li, Song-Zhe; Ohlemiller, Kevin K et al. (2014) Systemic lipopolysaccharide induces cochlear inflammation and exacerbates the synergistic ototoxicity of kanamycin and furosemide. J Assoc Res Otolaryngol 15:555-70
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
Hirose, Keiko; Sato, Eisuke (2011) Comparative analysis of combination kanamycin-furosemide versus kanamycin alone in the mouse cochlea. Hear Res 272:108-16