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）是一个普遍和日益严重的健康问题，但基本的细胞知识