Understanding the role of stress hormones in Meniere's disease - PROJECT SUMMARY Hearing loss and vertigo are symptoms of Meniere's disease (MD). While the etiology of MD is unknown, endolymphatic hydrops observed in the temporal bone specimens of MD patients point to disruption of endolymph homeostasis in the disease. The endolymph is an extracellular physiological fluid in the inner ear that is essential for hearing and balance. Consequently, any factor that perturbs the endolymph homeostasis is likely to affect inner ear function. However, our understanding of the factors that affect endolymph homeostasis is a work in progress. For example, we know stress is an important factor that exacerbates MD symptoms, but the relationship (molecular connection) between stress and endolymph homeostasis is unknown. Hence, a deeper understanding of the factors that affect endolymph homeostasis will be essential to develop effective treatments. This proposal will test the hypothesis that stress hormones affect endolymph production and inner ear physiology. Specific Aim 1 will focus on the role of adrenergic (stress) hormone receptors in endolymph homeostasis. To elucidate the action of adrenergic hormones on endolymph production, Aim 1a will focus on in vivo regulation of the endolymph and perilymph by adrenergic hormone receptors in mice. We will use various electrophysiological measures and histological analysis to assess the impact of these receptors on endolymph homeostasis and inner ear function. In Aim 1b, we will use explants from the mouse cochlea to analyze the physiologic response (to melatonin and β-adrenergic hormones) elicited by the stria vascularis in the cochlea and dark cells of the vestibular system, the epithelia responsible for the endolymph production. The physiological response will be evaluated by live imaging of ion levels in the cells of the explants. Specific Aim 2 will determine the action of glucocorticoids on endolymph homeostasis. This aim is important for two reasons. Glucocorticoid secretion is a classic endocrine response to stress, and injection of glucocorticoids is a common treatment for MD. In Aim 2, conditional knockout mice will be used to study the effect of (disabling) glucocorticoid receptors in intermediate cells of the stria vascularis. The outcomes will be assessed by methods used in Aim 1a. The proposed work will reveal the mechanistic relationship between stress hormones, endolymph homeostasis, and inner ear dysfunction. The results will be relevant to understanding the contributions of stress hormones to MD symptoms and developing treatments to mitigate those symptoms. Further, this award will launch the candidate to pursue an independent career in inner ear homeostasis. Case Western Reserve University will bring together expert physiological recording (Dr. Moss, consultant) and ion level imaging (Dr. Stepanyan, consultant) to enhance the candidate's career.
