Although glucocorticoids, such as prednisone, have been employed for decades for control of hearing loss, little is known of the cellular mechanisms of the ear that are under their control. A better understanding of these steroid responsive mechanisms is criticai for our design of appropriate therapy. Therefore, the long term goal of this research is to characterize the steroid driven cellular mechanisms of the ear. Preliminary studies have shown hearing loss in the MRL/MpJ-Fas(lpr) autoimmune mouse responds to treatment with both the glucocorticoid prednisolone and the mineralocorticoid aldosterone. It is hypothesized that two steroid responsive mechanisms exist in the ear: a direct sodium transport effect in the stria vascularis mediated by the mineralocorticoid receptor, and an indirect systemic immune suppression mechanism mediated by the glucocorticoid receptor. The planned studies will characterize these steroid driven processes with steroid treatments that will selectively isolate and measure the cellular and molecular events they control.
The specific aims to investigate these steroid mechanisms of the ear are:
Aim 1 : Establish the lowest effective dose of the mineralocorticoid and glucocorticoid for control of inner ear function and systemic autoimmune disease.
Aim 2 : Determine the lowest combination dose of the two steroids that can effectively control the inner ear dysfunction and systemic autoimmune disease.
Aim 3 : Determine which steroid receptor is mediating steroid control of cochlear function.
Aim 4 : Determine if the middle ear route of steroid delivery is a feasible treatment for either steroid control of autoimmune hearing loss.In all studies, assessment will be made of steroid effects on inner ear structure (light and electron microscopy), function (ABR, EP), cochlear specific antibodies (ELISA), and upregulated gene products (ELISA). The results from these studies will provide significant new findings regarding the cellular and molecular mechanisms of the ear that are under the control of steroids. This study also will lay important groundwork for the development of alternative steroid therapies that may be more effective than those currently employed for clinical hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC005593-01
Application #
6506784
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Watson, Bracie
Project Start
2002-07-22
Project End
2005-06-30
Budget Start
2002-07-22
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$298,962
Indirect Cost
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
MacArthur, Carol; Hausman, Fran; Kempton, Beth et al. (2015) Intratympanic Steroid Treatments May Improve Hearing via Ion Homeostasis Alterations and Not Immune Suppression. Otol Neurotol 36:1089-95
Quintanilla-Dieck, Lourdes; Larrain, Barbara; Trune, Dennis et al. (2013) Effect of systemic lipopolysaccharide-induced inflammation on cytokine levels in the murine cochlea: a pilot study. Otolaryngol Head Neck Surg 149:301-3
Tokarz, Sara A; Pang, Jiaqing; Grosz, Anna et al. (2013) Age-related cochlear cytokine gene expression in the BALB/cJ mouse with systemic versus intratympanic dosing of steroid drugs. Acta Otolaryngol 133:685-91
MacArthur, Carol J; Hausman, Fran; Kempton, J Beth et al. (2013) Inner ear tissue remodeling and ion homeostasis gene alteration in murine chronic otitis media. Otol Neurotol 34:338-46
Morris, Lisa M; DeGagne, Jacqueline M; Kempton, J Beth et al. (2012) Mouse middle ear ion homeostasis channels and intercellular junctions. PLoS One 7:e39004
MacArthur, C J; Hausman, F; Kempton, B et al. (2012) Otitis media: molecular impact of inflammation in the middle and inner ear--cytokines, steroids, and ion homeostasis. Laryngoscope 122 Suppl 4:S59-60
Trune, Dennis R; Canlon, Barbara (2012) Corticosteroid therapy for hearing and balance disorders. Anat Rec (Hoboken) 295:1928-43
Trune, Dennis R; Nguyen-Huynh, Anh (2012) Vascular Pathophysiology in Hearing Disorders. Semin Hear 33:242-250
MacArthur, Carol J; Hausman, Frances; Kempton, Julia Beth et al. (2011) Murine middle ear inflammation and ion homeostasis gene expression. Otol Neurotol 32:508-15
Trune, Dennis R; Larrain, Barbara E; Hausman, Frances A et al. (2011) Simultaneous measurement of multiple ear proteins with multiplex ELISA assays. Hear Res 275:1-7

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