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)是一个普遍且日益严重的健康问题，但基础细胞知识 涉及NIHL和潜在的内源性保护性信号系统的过程仍然不完整。 最初的，也是仍然占主导地位的耳蜗保护模式是基于橄榄耳蜗系统的活动，但 其他信号系统，包括下丘脑-垂体-肾上腺(HPA)轴也被认为是 保护耳蜗免受声学损伤。对这两种模式提出了重要的警告 然而，对耳蜗的保护。令人担忧的主要问题是刺激的强度和时间 激活信号，以及保护效果发生的时间进程。我们最近公布的数据表明 耳蜗会受到局部神经内分泌的控制。所有主要的信号分子都沿着经典的 HPA轴也表达并完全包含在耳蜗细胞内。这一数据强烈表明 存在局部活跃的HPA等效应力轴。我们的初步数据表明 当促肾上腺皮质激素释放时，耳蜗会同时释放皮质酮和醛固酮。 因子(CRF)和促肾上腺皮质激素(ACTH)，这两个我们之前已经证明是 在耳蜗处表达。我们以前也证明了CRF信号在COCH中起着不可或缺的作用。 莉亚。烧蚀CRFR1的灵敏度损失25dB，而烧蚀CRFR2的灵敏度增加20db 敏感性，同时增加对低至50dBSPL暴露后ABR阈值漂移的敏感性 鉴于目前的耳蜗保护模式对其激活要求的相关警告- 我们的数据表明，耳蜗轴在较低强度时可能是活跃的 我们认为，这种相当于耳蜗HPA的信号系统代表了一种新的、普遍存在的信号系统。 极不为人所知的因素，与耳蜗保护有关。为了测试耳蜗是否使用类似HPA的信号- 为了保护，需要更多关于耳蜗胞内应激的基本信息 轴心。例如，该系统是否由声音激活，以及它是否具有选择性仍未得到证实 激活可以预防NIHL。这些未知因素阻碍了人们对耳蜗的深入了解。 发信号。我们的假设是，耳蜗轴作为一个独立的局部(快速反应)神经元- 由声音激活的内分泌控制系统，有助于调节敏感度和压力- 暴露于破坏性刺激后，通过局部类固醇激素释放的反应。我们将追查两个特种部队- 设计的目的是：1)识别耳蜗中接收CRF信号并有能力产生CRF的细胞 类固醇激素和确定释放是否声音诱发；和2)测试选择性激活的能力 耳蜗CRF信号系统对NIHL的保护作用。来自该项目的数据将对 撰写竞争性R01，旨在检查特定细胞群中类固醇释放的作用。