An investigation into cochlear HPA like signaling

耳蜗 HPA 样信号传导的研究

• 批准号: 9027411
• 负责人: DOUGLAS E VETTER
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027411
• 关键词: Ablation; Acoustics; Adrenal Glands; Aldosterone; Apoptosis; Body part; CRH gene; Cell physiology; Cells; Cellular Stress; Cellular Stress Response; Cochlea; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Data; Elements; Endocrine; Enzyme-Linked Immunosorbent Assay; Enzymes; Exhibits; Exposure to; Frequencies; Funding; Future; Generations; Goals; Hair Cells; Health; Hearing; Hormones; Hypothalamic structure; Injury; Investigation; Knowledge; Labyrinth; Maintenance; Maps; Metabolic; Modeling; Nature; Nerve Fibers; Neurosecretory Systems; Noise; Noise-Induced Hearing Loss; Operative Surgical Procedures; Pituitary Gland; Play; Population; Predisposition; Process; Publishing; Reaction; Reactive Oxygen Species; Regulation; Research; Retina; Risk; Role; Services; Signal Transduction; Signaling Molecule; Skin; Steroids; Stimulus; Stress; Synapses; System; Temporary Threshold Shift; Testing; Therapeutic; Time; Tissues; Veterans; Work; Writing; base; biological adaptation to stress; biological systems; clinically significant; design; economic impact; expectation; experience; genetic approach; hearing impairment; high risk; hypothalamic-pituitary-adrenal axis; innovation; local drug delivery; new therapeutic target; normal aging; novel; prophylactic; protective effect; research study; response; signal processing; sound; steroid hormone; therapeutic target; therapy design

Noise-induced hearing loss (NIHL) is a pervasive and growing health problem, yet knowledge of basic cellular processes involved in both NIHL and potential endogenous protective signaling systems remain incomplete. The initial, and still predominant, model of cochlear protection is based on olivocochlear system activity, but other signaling systems, including the hypothalamic-pituitary-adrenal (HPA) axis also have been suggested to protect the cochlea against acoustic injury. Significant, caveats have been raised concerning these two models of cochlear protection, however. The main issues of concern are the intensity and time of stimuli required to activate signaling, and the time course for protective effects to occur. Our recently published data indicate that the cochlea is under local neuroendocrine control. All major signaling molecules expressed along the classic HPA axis are also expressed and completely contained within cells in the cochlea. This data strongly suggests the existence of a locally active HPA-equivalent cochlear stress axis. Our preliminary data demonstrate that the cochlea is capable of releasing both corticosterone and aldosterone in response to corticotropin releasing factor (CRF) and adrenocorticotropin hormone (ACTH), both of which we have previously demonstrated to be expressed in the cochlea. We have also previously shown that CRF signaling plays an integral role in the coch- lea. Ablation of CRFR1 produces a 25dB loss of sensitivity, while ablation of CRFR2 generates a 20dB gain of sensitivity, while increasing susceptibility to ABR threshold shifts following exposures as low as 50dB SPL Given the caveats related to current models of cochlear protection with respect to their requirement for activa- tion by high intensity sounds, and our data suggesting the cochlear stress axis may be active at lower intensity sound exposures, we propose that this cochlear HPA-equivalent signaling system represents a novel, previ- ously unrecognized element involved in cochlear protection. To test whether the cochlea uses an HPA-like sig- naling system for protection, more information is required concerning the basics of the cochlear cellular stress axis. For example, it remains unproven whether the system is activated by sound, and whether its selective activation can protect against NIHL. These unknowns are impediments to a deeper understanding of cochlea signaling. Our hypothesis is that the cochlear stress axis acts as an independent local (fast responding) neuro- endocrine control system activated by sound that contributes to the modulation of sensitivity and stress- responses via local steroid hormone release following exposure to damaging stimuli. We will pursue two spe- cific aims, designed to: 1) identify cells in the cochlea that receive CRF signaling and are competent to produce steroid hormones and to identify whether release is sound evoked; and 2) test the ability of selective activation of the cochlear CRF signaling system in protecting against NIHL. Data from this project will be important for writing a competitive R01 designed to examine the role of steroid release from specific cell populations.

噪声性听力损失 (NIHL) 是一个普遍存在且日益严重的健康问题，但对基本细胞的了解 NIHL 和潜在的内源性保护信号系统所涉及的过程仍然不完整。 最初且仍然占主导地位的耳蜗保护模型基于橄榄耳蜗系统活动，但是 其他信号系统，包括下丘脑-垂体-肾上腺（HPA）轴也被建议 保护耳蜗免受声损伤。关于这两种模型提出了重要的警告 然而，耳蜗保护。主要关注的问题是刺激的强度和时间 激活信号传导，以及保护作用发生的时间过程。我们最近发布的数据表明 耳蜗受局部神经内分泌控制。所有主要信号分子均沿经典表达 HPA 轴也表达并完全包含在耳蜗细胞内。该数据强烈表明 局部活跃的 HPA 等效耳蜗应力轴的存在。我们的初步数据表明 耳蜗能够响应促肾上腺皮质激素的释放而释放皮质酮和醛固酮 因子（CRF）和促肾上腺皮质激素（ACTH），我们之前已经证明它们是 表达于耳蜗。我们之前也表明 CRF 信号在耳蜗中发挥着不可或缺的作用。 莱。 CRFR1 的消融会产生 25dB 的灵敏度损失，而 CRFR2 的消融则会产生 20dB 的增益 灵敏度，同时增加暴露于低至 50dB SPL 后对 ABR 阈值变化的敏感性 考虑到与当前的耳蜗保护模型有关的关于激活的要求的警告 高强度声音的影响，我们的数据表明耳蜗应力轴可能在较低强度下活跃 声音暴露，我们提出这种耳蜗 HPA 等效信号系统代表了一种新颖的、先前的 与耳蜗保护有关的明显未被识别的元素。为了测试耳蜗是否使用类似 HPA 的信号， 保护系统，需要更多有关耳蜗细胞应激基础知识的信息 轴。例如，该系统是否是由声音激活的，以及它是否具有选择性，仍然未经证实。 激活可以预防 NIHL。这些未知因素阻碍了更深入了解耳蜗 发信号。我们的假设是耳蜗应力轴充当独立的局部（快速响应）神经元 由声音激活的内分泌控制系统有助于调节敏感性和压力- 暴露于破坏性刺激后通过局部类固醇激素释放做出反应。我们将追求两个特定 cific 的目标，旨在：1）识别耳蜗中接收 CRF 信号并能够产生 类固醇激素并确定释放是否是声音诱发的； 2）测试选择性激活的能力 耳蜗 CRF 信号系统在预防 NIHL 中的作用。该项目的数据对于 编写竞争性 R01，旨在检查特定细胞群释放类固醇的作用。