Hearing Preservation for Noise or Cochlear Implantation: Mechanisms & Treatments

描述（由申请人提供）：在过去十年中，最令人兴奋的进展之一是在压力条件下保持听力的治疗方法的发展，否则会导致毛细胞脱落。然而，目前的治疗方法侧重于保存感觉细胞，最近的研究结果（Kujawa和Liberman， 2006, 2009）表明，内毛细胞（IHC）和听神经（AN）之间的连接也可能有永久丧失的风险。我们提出的研究考察了两种具有高临床相关性的应激条件下IHC-AN连接的丧失：噪声性听力损失和保留听力的耳朵植入假体，然后测试抗氧化（AO）治疗的保护/恢复效果，最后确定在AO治疗中加入抗兴奋毒性治疗是否会改善IHC-AN连接和听力的保护/恢复。目的1：验证一种假设，即引起许多毛细胞永久性损失的适度噪声也会导致许多IHC-AN连接在剩余ihc上的永久性损失，并随后导致听觉神经元（SGN）的损失。目的2-验证假设（2a），即有效减少噪声诱导的毛细胞损失的AO治疗在减少IHC-AN连接损失方面效果较差；（2b）添加特定的抗兴奋毒性治疗将改善IHC-AN连接的保存、SGN的长期存活和听力。目的3：验证假体植入听力正常的耳朵所造成的创伤会导致IHC-AN连接的丢失，包括毛细胞未丢失的区域。目的4 -验证假设（4a）添加AO治疗将比添加假体插入创伤的IHC-AN连接更有效地保存毛细胞；（4b）在AO治疗中添加特异性抗兴奋毒性治疗将改善IHC-AN连接的保存。目的5 -验证减少IHC-AN连接和SGN的损失将改善听觉和对人工耳蜗刺激的心理物理反应的时空敏锐度的假设。所提出的研究结果将重新定义和扩大保留听力的治疗目标，不仅对治疗被测试的两种情况（噪声性听力损失和耳蜗假体植入）具有高影响，而且对其他内耳病变（从耳毒性到前庭疾病）的最佳治疗实践具有高度相关性。如果成功，一种新的治疗模式可以直接转化为临床试验，并使全世界数百万人受益。

DESCRIPTION (provided by applicant): One of the most exciting advances in the last decade has been the development of therapies to preserve hearing under conditions of stress that can otherwise cause hair cell loss. Current therapies, however, focus on preservation of sensory cells and recent results (Kujawa and Liberman, 2006, 2009) indicate that the connections between inner hair cells (IHC) and auditory nerve (AN) may also be at risk for permanent loss. Our proposed studies examine loss of IHC-AN connections during two stresses chosen for high clinical relevance: Noise Induced Hearing Loss and Prostheses Insertion in Ears with Remaining Hearing, then test the efficacy of anti-oxidant (AO) therapy for protection / recovery and finally determine if adding anti- excitotoxicity therapy to the AO therapy will improve protection / recovery of IHC-AN connections and hearing. Aim 1-Test the hypothesis that a moderate noise causing permanent loss of many hair cells will also produce a permanent loss of many IHC-AN connections on remaining IHCs and later loss of auditory neurons (SGN). Aim 2- Test the hypothesis (2a) that AO treatments that effectively reduce noise-induced hair cell loss will be less effective in reducing the loss of IHC-AN connections and (2b) that adding a specific anti-excitotoxicity therapy will improve preservation of IHC-AN connections, long term survival of SGN and hearing. Aim 3 - Test the hypothesis that trauma from insertion of a prostheses into a hearing ear will induce loss of IHC-AN connections, including in regions where hair cells are not lost. Aim 4 - Test the hypothesis (4a) that adding AO treatment will be more effective in preserving hair cells than IHC-AN connections from the trauma of prostheses insertion and (4b) addition of specific anti-excitotoxicity therapy to the AO therapy will improve the preservation of IHC-AN connections. Aim 5 - Test the hypothesis that reducing loss of IHC-AN connections and SGN will improve acoustic hearing and spatial and temporal acuity of psychophysical responses to cochlear implant stimulation. Results of the proposed studies will redefine and broaden treatment targets for preserving hearing with high impact not only toward treating the two conditions being tested, noise-induced hearing loss and implantation of cochlear prostheses into ears with remaining hearing, but with high relevance towards best treatment practices for other inner ear pathologies ranging from ototoxicity to vestibular disorders. If successful, a new treatment paradigm can be directly translated to clinical trials and benefit millions of individuals worldwide. PUBLIC HEALTH RELEVANCE: Our proposed studies are to develop and test better treatments to preserve hearing during two traumatic stresses to the ear, chosen for high clinical relevance: Noise Induced Hearing Loss and Prostheses Insertion in Ears with Remaining Hearing.