# Macrophage Response to Otic Pathology

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $433,405

## Abstract

The senses of hearing and balance are mediated by the cochlea and vestibular organs of the inner ear. In
these organs, mechanical motion (generated either by sound vibrations or by head movements) is detected by
sensory hair cells and transmitted to the brain by the auditory and vestibular nerves. Hair cells are essential for
sensory function, but can be injured by noise exposure, ototoxicity or infections, and are also lost as a
consequence of normal aging. After injury, the timely removal of cellular debris from the sensory epithelium
helps promote repair and homeostasis. This process is mediated by two distinct cell types: (1) Supporting cells,
which can engulf cellular debris and – in nonmammalian vertebrates – generate replacement hair cells, and (2)
Macrophages, which are effector cells of the innate immune system that also recognize and engulf dying cells.
Supporting cells are present in all hair cell-containing epithelia. The tissues of the inner ear also contain
resident populations of macrophages, and macrophage-mediated inflammation occurs after most types of otic
injury. When responding to hair cell injury, it is critical that both supporting cells and macrophages correctly
distinguish between healthy and dying cells, and then target and remove only those cells that are irreversibly
damaged. A key objective of this project is to understand how this process occurs. One set of experiments will
examine a signaling pathway known to be essential for evoking phagocytic responses in macrophages and
other cell types, but has not been previously studied in the inner ear. In addition, we will determine whether
inhibiting phagocytosis after acute injury may permit some damaged hair cells to survive, and whether the
engulfment of injured hair cells is an important trigger for sensory regeneration. Studies will employ both
mammalian and zebrafish models, in order to best utilize the unique advantages of both systems. A second set
of experiments will enhance our very limited knowledge of the role of inflammation in the vestibular organs.
Projects will focus on two clinically relevant situations. First, it is known that prenatal infection with
cytomegalovirus (CMV) can cause developmental deficits in both hearing and balance, but the underlying
mechanisms are completely unknown. Using a validated mouse model, we have shown that CMV infection
leads to a massive inflammatory response in the vestibular maculae, which is accompanied by phagocytosis of
sensory cells. We will determine whether this inflammation is the cause of CMV-induced pathology and also
whether macrophages transport CMV into the vestibular periphery. Additional studies will characterize
vestibular injury and inflammation in a mouse model of cochlear implantation. Completion of the studies will
greatly enhance current knowledge of the cellular signals that regulate inflammation in the inner ear. Such
knowledge will permit development of methods for modulating such inflammation, so as t...

## Key facts

- **NIH application ID:** 10889035
- **Project number:** 5R01DC006283-18
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Mark Warchol
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $433,405
- **Award type:** 5
- **Project period:** 2004-04-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889035

## Citation

> US National Institutes of Health, RePORTER application 10889035, Macrophage Response to Otic Pathology (5R01DC006283-18). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10889035. Licensed CC0.

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