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.

噪声引起的听力损失（NIHL）是一个普遍且越来越多的健康问题，但对基本细胞的了解 NIHL和潜在的内源性保护信号系统涉及的过程仍然不完整。 人工耳蜗保护的初始且仍然是主要的模型是基于橄榄石系统的活动，但 还建议其他信号系统，包括下丘脑 - 垂体 - 肾上腺（HPA）轴 保护耳蜗免受声损伤。关于这两个模型已经提出了重要的警告 但是，人工耳蜗保护。关注的主要问题是刺激的强度和时间 激活信号传导和防护效果的时间过程。我们最近发布的数据表明 该耳蜗处于局部神经内分泌控制之下。沿经典表达的所有主要信号分子 HPA轴也表达并完全包含在耳蜗中的细胞中。这些数据强烈建议 存在局部活跃的HPA等效的耳蜗应力轴的存在。我们的初步数据表明 该耳蜗能够响应皮质激素释放来释放皮质酮和醛固酮 因子（CRF）和肾上腺皮质激素激素（ACTH），我们以前都证明这两个激素 在耳蜗中表达。我们以前还表明，CRF信号在Coch-中起着不可或缺的作用 Lea。 CRFR1的消融会产生25dB的灵敏度丧失，而CRFR2的消融产生20dB的增益 敏感性，同时增加对ABR阈值的敏感性低至50dB SPL 考虑到与当前的人工耳蜗保护模型有关的警告，就其对Activa-的要求 高强度的声音，我们的数据表明耳蜗应力轴可能在较低的强度下活跃 声音暴露，我们建议这种人工耳蜗HPA等效的信号系统代表了一种新颖的，预先的 涉及人工耳蜗保护涉及的元素。测试耳蜗是否使用类似于HPA的sig- 用于保护系统，需要更多有关人工耳蜗应力基础知识的信息 轴。例如，是否通过声音激活系统以及是否有选择性 激活可以预防NIHL。这些未知数是对耳蜗更深入了解的障碍 信号。我们的假设是，耳蜗应力轴是独立的局部（快速响应）神经 - 由声音激活的内分泌控制系统有助于调节灵敏度和应力 - 暴露于破坏性刺激后，通过局部类固醇激素释放的反应。我们将追求两个Spe- 旨在：1）识别接收CRF信号并有能力生产的耳蜗中的细胞识别细胞 类固醇激素，并确定是否唤起了释放的声音； 2）测试选择性激活的能力 在防止NIHL保护的人工耳蜗CRF信号系统中。该项目的数据对于 编写竞争性R01，旨在检查特定细胞种群中类固醇释放的作用。