# ALTERATIONS OF SPHINGOLIPID SIGNALING AND MACROPHAGE FUNCTION IN AGE-RELATED HEARING LOSS

> **NIH NIH F31** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $2,101

## Abstract

PROJECT SUMMARY
This proposal aims to identify alterations in cochlear macrophages and how these cellular changes correlate with
the progression of metabolic presbyacusis (strial presbyacusis). Metabolic presbyacusis is a form of age-related
hearing loss resulting from degeneration of the stria vascularis. During aging, the strial microvasculature (StvM)
has been observed to degenerate, leaving avascular regions. Although StvM loss is closely associated with
declines in auditory function, the cellular and molecular mechanisms mediating this pathology are currently
unknown. Macrophages have been observed to reside in the stria vascularis, making close contacts with strial
vessels and playing a role in regulating their permeability. Our preliminary data shows that macrophages undergo
morphological and transcriptomic changes in the stria vascularis with age, suggestive of an activated state that is
pro-inflammatory and may contribute to the cochlear pathology of metabolic presbyacusis. Sphingosine-1-
phosphate and its receptor (S1P/S1PR) signaling plays a significant role in determination of macrophage activity
where high levels of the bioactive signaling molecule, S1P, polarizes macrophages to an anti-inflammatory state.
Preliminary gene expression analysis for proteins that regulate S1P synthesis have identified molecular
perturbations consistent with a reduction of S1P synthesis in the aged cochlear lateral wall. Our overarching
hypothesis is that age-related macrophage dysfunction and associated alterations of S1P/S1PR signaling
contribute to strial microvasculature pathology, EP reduction, and auditory function declines. In Aim 1,
we will test the hypothesis that age-related macrophage dysfunction is characterized by a shift towards pro-
inflammatory activity. Morphological and molecular measures of macrophage activation will be employed to define
macrophage dysfunction in the aging stria vascularis. Gene expression analysis of macrophages will be used to
define the transcriptomic profile of these activated immune cells with age in the cochlea. In Aim 2, we will test
the hypothesis that disruption of S1P/S1PR signaling contributes to macrophage dysregulation in the aged
cochlear lateral wall resulting in EP reduction and associated auditory function declines. Macrophage morphology
and activation state will be assessed in a mouse model of disrupted S1P/S1PR signaling along with the
determination of the effects on overall cochlear lateral wall and auditory function. This study will identify molecular
markers of macrophage dysfunction and assess the contribution of altered S1P/S1PR signaling to the pathology
of metabolic presbyacusis. Findings from this study will have implications regarding the role of immune cells and
S1P/S1PR signaling in metabolic presbyacusis and offer new potential therapeutic targets for treatment. The
mentoring team, training plan, and fellowship goals outlined in the proposal will prepare the applicant for a career
as an ...

## Key facts

- **NIH application ID:** 10073497
- **Project number:** 5F31DC017665-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Kenyaria Vashay Noble
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,101
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-01-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073497

## Citation

> US National Institutes of Health, RePORTER application 10073497, ALTERATIONS OF SPHINGOLIPID SIGNALING AND MACROPHAGE FUNCTION IN AGE-RELATED HEARING LOSS (5F31DC017665-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073497. Licensed CC0.

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