Steroid Responsive Mechanisms in the Ear

描述（由申请人提供）：虽然糖皮质激素，如强的松，几十年来一直被用于控制听力损失，但人们对其控制下的耳细胞机制知之甚少。更好地了解这些类固醇反应机制对我们设计适当的治疗至关重要。因此，本研究的长期目标是表征类固醇驱动的耳细胞机制。初步研究表明，MRL/MpJ-Fas（lpr）自身免疫小鼠的听力损失对糖皮质激素强的松龙和矿皮质激素醛固酮治疗均有反应。假设耳内存在两种类固醇反应机制：一种是矿皮质激素受体介导的血管纹内钠的直接转运作用，另一种是糖皮质激素受体介导的间接全身免疫抑制机制。计划中的研究将用类固醇治疗来表征这些类固醇驱动的过程，选择性地分离和测量它们控制的细胞和分子事件。目的1：确定矿皮质激素和糖皮质激素的最低有效剂量，以控制内耳功能和全身自身免疫性疾病。目的2：确定能有效控制内耳功能障碍和全身自身免疫性疾病的两种类固醇的最低联合剂量。目的3：确定哪种类固醇受体介导耳蜗功能的类固醇控制。目的4：确定中耳类固醇输注是否是类固醇控制自身免疫性听力损失的可行治疗方法。在所有研究中，将评估类固醇对内耳结构（光镜和电镜）、功能（ABR、EP）、耳蜗特异性抗体（ELISA）和上调基因产物（ELISA）的影响。这些研究结果将为类固醇控制下的耳细胞和分子机制提供重要的新发现。这项研究也将为开发替代类固醇疗法奠定重要的基础，这些疗法可能比目前用于临床听力损失的疗法更有效。

DESCRIPTION (provided by applicant): 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.