# Calcium Binding Proteins Regulate Susceptibility to Damage in the Inner Ear

> **NIH NIH R15** · BAYLOR UNIVERSITY · 2021 · $420,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Approximately 15% of Americans have high frequency hearing loss caused by exposure to loud sounds and
50% of Americans over 75 years old are affected by presbycusis. Although substantial progress has been
made in determining the genetic and cellular functions disrupted by acquired hearing loss, comparatively little
is known about the endogenous cellular and molecular mechanisms used to protect cochlear hair cells from
the damaging effects of aging and noise. The long-term objective of this research is to investigate the role of
mobile Ca2+ buffers in the inner ear especially during development and aging. It is our contention that
understanding maturational processes that occur during development may provide important cues to
understanding attempts to repair damage during aging. In the cochlea, outer hair cells (OHCs) act as sentinels
of cochlear injury. Calcium regulation is fundamentally important to OHC development, function and aging. This
proposal focuses on the development and age-related role of oncomodulin (OCM), a major Ca2+-binding
protein preferentially expressed in OHCs. We hypothesize that OCM is necessary for the maturation of calcium
signaling in OHCs and protects OHCs from the damaging effects of cellular stress. Specific Aim 1 determines
the role OCM has in regulating Ca2+ signaling in pre-hearing and post-hearing OHCs. We will use Ca2+
imaging techniques and organotypic and cell culture methods to address the following hypotheses: 1. OCM
shortens Ca2+ signaling kinetics and magnitudes in pre- and post-hearing OHCs; 2. OCM modulates the
expression of other proteins involved in OHC Ca2+ signaling; 3. OCM Ca2+ signaling depends on the Ca2+
source. Specific Aim 2 tests whether OCM mediates sensitivity to aging and noise. Using in vivo
functional assays assessing cochlear thresholds (ABRs and DPOAEs) and light, confocal and electron
microscopy in Ocm mutant mice, we will investigate the following hypotheses: 1. targeted deletion of Ocm
accelerates ARHL independent of genetic strain leading to decreased suprathreshold responses, loss of OHC
cholinergic efferent synapses, and cell death; 2. OCM deficiency makes OHCs more susceptible to damage
after cochlear injury. Specific Aim 3 tests whether OCM modulates Ca2+-mediated cellular stress and
promotes cell survival. Using qRT-PCR, western blots, and immunocytochemistry in wild-type and mutant
ears and in transfected cell lines, we will investigate the following hypotheses: 1. In response to stress, OCM
translocates from cytoplasm to the nucleus ; 2. OCM modulates cellular responses to mitochondrial stress; and
3. OCM intracellular location and modulation of cell stress promote overall cell survival. In summary, these
studies on OCM provide new tools that should significantly enhance our understanding of the role of Ca2+
regulation in protecting auditory function. Undergraduates will play significant roles roles in the collection and
analysis of data of each aim.

## Key facts

- **NIH application ID:** 10202072
- **Project number:** 1R15DC018935-01A1
- **Recipient organization:** BAYLOR UNIVERSITY
- **Principal Investigator:** DWAYNE D SIMMONS
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,000
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202072

## Citation

> US National Institutes of Health, RePORTER application 10202072, Calcium Binding Proteins Regulate Susceptibility to Damage in the Inner Ear (1R15DC018935-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10202072. Licensed CC0.

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