# Middle Ear Response in Otitis Media

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $329,375

## Abstract

PROJECT SUMMARY / ABSTRACT
Otitis media is one of the largest public health problems of young children in the United States, and also
contributes to half of the world's burden of hearing loss and 28,000 annual deaths worldwide. Otitis media is
thought to be a multifactorial condition that can be induced by a variety of inciting events. However, once
initiated, otitis media often converges upon a final common pathway of inflammation, effusion and tissue
hyperplasia that in turn can produce temporary or permanent hearing loss. Upon resolution of otitis media the
hyperplastic middle ear mucosa can recover to a condition at or close to its original structure, although
permanent changes including fibrosis and osteoneogenesis can occur. The long-term goal of this project is to
understand host responses in the middle ear during otitis media, with a particular focus on the transformation
of the middle ear mucosa from a resting state into a highly active, hyperplastic structure that contributes to both
host defense and pathogenesis. During the current period of support we have discovered two novel mediators
that play significant roles in mucosal hyperplasia and inflammation. Based on our observation of the properties
of these two mediators in the middle ear, we propose a new model of host responses in otitis media. In this
model, the transmembrane tissue gowth suppressor and sentinel protein ECRG4 inhibits mucosal hyperplasia
and inflammation in the normal middle ear. Bacterial infection induces cleavage of the exracellular domain of
ECRG4 to release an 8 kDa fragment. Cleavage inactivates full-length ECRG4, releasing the mucosa from
growth inhibition, and also allowing production of the leukocyte extravasation factor CD44. In addition, the
dual-function 8 kDa fragment induces mucosal tissue hyperplasia and also binds to the TLR4/MD2/CD14
endotoxin receptor complex to enhance its activation. Activation of NFkB by the receptor induces expression
of HB-EGF, which also further induces mucosal hyperplasia. We will test this model by manipulating the
expression of ECRG4, CD44 and HB-EGF. The ultimate goal of this research is to identify new targets for
pharmacological manipulation that will reduce otitis media pathogenesis and enhance recovery.

## Key facts

- **NIH application ID:** 10200746
- **Project number:** 5R01DC000129-41
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Allen F. Ryan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $329,375
- **Award type:** 5
- **Project period:** 1990-04-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200746

## Citation

> US National Institutes of Health, RePORTER application 10200746, Middle Ear Response in Otitis Media (5R01DC000129-41). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10200746. Licensed CC0.

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