Although glucocorticoids 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. Knowledge of these steroid-responsive mechanisms is critical for our understanding of normal cochlear function, as well as the design of appropriate clinical therapies. Therefore, the long term goal of this research is to fully characterize the steroid-driven cellular and molecular mechanisms of the ear. Progress on this study has shown that hearing loss in the MRL/MpJ-Fas1pr autoimmune mouse responds to steroid treatments by regulating cochlear gene expression with both the glucocorticoid prednisolone and the mineralocorticoid aldosterone. Therefore, our working hypothesis is that two steroid-responsive mechanisms exist in the ear: a direct sodium and potassium transport (homeostatic) gene expression mediated by the mineralocorticoid receptor, and an indirect inflammatory gene suppression mechanism mediated by the glucocorticoid receptor. The planned studies will characterize these steroid driven cellular and molecular processes with steroid treatments that will selectively isolate these receptors and measure changes in cochlear homeostatic and inflammatory genes and proteins they control.
The specific aims to investigate these steroid mechanisms of the ear are:
Aim 1 : Determine the dose-dependent control of inner ear ion homeostatic and inflammatory gene expression by the mineralocorticoid aldosterone and the glucocorticoid prednisolone.
Aim 2 : Determine the most effective control of both inner ear ion homeostatic and inflammatory gene expression processes by combination doses of the two steroids.
Aim 3 : Determine which cochlear cellular and molecular functions are mediated by each steroid receptor.
Aim 4 : Determine if effective inner ear homeostatic and anti-inflammatory gene expression can be induced by middle ear steroid delivery. In all studies, 1) inner ear function will be assessed by auditory brainstem response audiometry. The endocochlear potential will be measured in some experiments. 2) inner ear morphology will be assessed by light and electron microscopy; 3) systemic autoimmune disease will be assessed by serum immune complexes, hematocrits, and antinuclear antibodies; 4) cochlear specific autoantibodies will be assessed with ELISA, and 5) steroid-mediated cochlear gene products will be assessed with ELISA, Western blot, cytokine RNA expression, and quantitative RT-PCR. The results from these studies will provide new findings regarding the cellular and molecular mechanisms of the ear that are under the control of steroids. This also will lay important groundwork for the potential development of steroid therapies more effective than those currently employed.
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