# Project 2:  Mechanistic studies of age-related hearing loss using animal models and human tissue

> **NIH NIH P50** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $412,778

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 2
 Age-related hearing loss (presbyacusis) is a common neurodegenerative disorder that can be
associated with loss and/or dysfunction of several specialized cell types in the cochlear lateral wall (metabolic
presbyacusis) and the auditory nerve (neural presbyacusis). Project 2 of the Clinical Research Center aims to
identify critical cellular and molecular mechanisms underlying human metabolic and neural presbyacusis using
mouse models and post-mortem human temporal bones from younger and older donors. Dysregulation of
microglia/macrophages and the complement cascade, two fundamental elements of the innate immune
system, have been shown to play vital roles in several age-related neurodegenerative disorders. Our
preliminary studies have revealed that cochlear macrophages may undergo structural and molecular
alterations with increasing age, indicative of functional changes, and that these alterations are associated with
pathological changes in the cochlear lateral wall microvasculature of aged mice. Sphingosine-1-phosphate
(S1P), a lipid signaling molecule, regulates macrophage activity. Preliminary studies of gene expression
patterns and age-related macrophage dysfunction in mouse cochlear tissue suggest a link between a reduction
in S1P bioavailability with increasing age and macrophage dysfunction in the cochlear lateral wall. In addition,
differential gene expression analysis in the mouse auditory nerve has identified major changes with increasing
age in the innate immune response and complement cascade pathways. Recent studies of other
neurodegenerative disorders have shown that complement dysregulation can lead to demyelination and neural
degeneration. Based on these observations, our overarching hypothesis is that age-dependent dysregulation
of the cochlear innate immune system contributes to the degeneration of specialized cells in the aging lateral
wall and auditory nerve, leading to declines in auditory function consistent with metabolic and neural
presbyacusis. Project 2 will 1) determine the relationship between S1P-mediated macrophage dysfunction and
strial microvasculature degeneration in the lateral wall of aged mice (Aim 2.1); and 2) elucidate the links
between age-related dysregulation of the complement system with degeneration and functional declines in
auditory nerve fibers, in particular fibers with low spontaneous rates (Aim 2.2). Animal models of lateral wall
and auditory nerve degeneration characterized in Project 2 will also be used to validate genetic and
pathophysiology results obtained from human subjects studied in Projects 1, 3, and 4. Comparative studies of
the expression patterns of these key immune response regulatory molecules will also be examined in human
temporal bones, which are accessed through the Human Subjects Core (Core B). The ability to compare
results from animal models, human temporal bones, and human subjects provides an unparalleled opportunity
to address questions r...

## Key facts

- **NIH application ID:** 10470232
- **Project number:** 5P50DC000422-34
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Hainan Lang
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $412,778
- **Award type:** 5
- **Project period:** 1997-07-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470232

## Citation

> US National Institutes of Health, RePORTER application 10470232, Project 2:  Mechanistic studies of age-related hearing loss using animal models and human tissue (5P50DC000422-34). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10470232. Licensed CC0.

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