Otitis media (OM) is a major health problem, resulting in substantial health care expenditures. More than 90% of children experience OM. While acute, uncomplicated OM tends to be self-limiting, 10- 20% of children experience persistent, recurrent or chronic disease. The long-lasting forms of this condition produce hearing loss during critical periods of language acquisition and learning, and carry a risk for permanent damage to the middle and inner ear. Current treatments, including prophylactic or repeated antibiotics and surgical interventions, are controversial, underscoring the need for additional therapies. The causes of persistent OM, and why some children progress to persistent or recurrent disease while others experience only one or a few episodes of acute OM, are not clear. However, mechanisms that contribute to other forms of chronic inflammatory diseases have recently been identified. These include mutations or polymorphisms in genes that subserve innate immunity, defects in cellular processes that control infection such as phagocytosis, and dysregulation of cellular and tissue systems that promote recovery from inflammation. Data obtained during the current period of support suggest the involvement of these mechanisms in persistent OM, as well. OM in mice with mutations in several innate immune genes fail to recover normally from OM. Moreover, OM persistence is correlated with changes in the behavior and function of macrophages. Finally, genes encoding pro-recovery monocyte phenotypes, as well as pro-recovery factors and their receptors, are up-regulated during the recovery phase of OM. In this application Drs. Stephen Wasserman, Allen Ryan and Eyal Raz propose a series of integrated experiments employing genetically modified mice to identify cellular and molecular mechanisms that lead to chronic OM, and to explore novel therapies for this condition.
Aim 1 of this application will assess the contributions of innate immune NOD-like receptor (NLR) signaling pathways to OM pathogenesis and recovery.
Aim 2 will investigate the role of different phenotypes of monocyte-derived cells, including macrophages and dendritic cells, in OM.
Aim 3 will elucidate the mechanisms by which recovery from inflammation is regulated in the middle ear (ME), and determine whether pro-recovery factors can ameliorate acute and persistent ME disease. Together these studies will expand our understanding of how OM recovery can fail, and how this failure can be reversed.

Public Health Relevance

Otitis media is the most common disease in young children, accounting for more office visits and surgery than any other childhood condition and costing an estimated five billion dollars. Moreover, chronic and recurrent middle ear disease leads to hearing loss during critical periods of language acquisition and learning, with a risk of language delay and learning difficulties and permanent damage to the middle and inner ear. The proposed research will increase our understanding of otitis media and why it becomes chronic, and will explore new forms of therapy for this condition.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006279-08
Application #
8246473
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Watson, Bracie
Project Start
2003-07-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$317,807
Indirect Cost
$112,107
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Kurabi, Arwa; Lee, Jasmine; Wong, Chelsea et al. (2015) The inflammasome adaptor ASC contributes to multiple innate immune processes in the resolution of otitis media. Innate Immun 21:203-14
Hernandez, Michelle; Leichtle, Anke; Pak, Kwang et al. (2015) The transcriptome of a complete episode of acute otitis media. BMC Genomics 16:259
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Yao, William; Frie, Meredith; Pan, Jeffrey et al. (2014) C-Jun N-terminal kinase (JNK) isoforms play differing roles in otitis media. BMC Immunol 15:46
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Kurabi, Arwa; Pak, Kwang; Dang, Xitong et al. (2013) Ecrg4 attenuates the inflammatory proliferative response of mucosal epithelial cells to infection. PLoS One 8:e61394
Souter, Melanie; Eastwood, Hayden; Marovic, Paul et al. (2012) Systemic immunity influences hearing preservation in cochlear implantation. Otol Neurotol 33:532-8
Husseman, Jacob; Palacios, Sean D; Rivkin, Alexander Z et al. (2012) The role of vascular endothelial growth factors and fibroblast growth factors in angiogenesis during otitis media. Audiol Neurootol 17:148-54

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