Hearing Preservation for Noise or Cochlear Implantation: Mechanisms & Treatments

描述(申请人提供)：在过去的十年中，最令人兴奋的进步之一是在压力条件下保护听力的治疗方法的发展，否则可能会导致毛细胞丧失。然而，目前的治疗方法侧重于感觉细胞的保存，最近的结果(Kujawa和Liberman，2006,2009)表明，内毛细胞(IHC)和听神经(AN)之间的连接也可能面临永久丧失的风险。我们建议的研究检查在两种高临床相关性的压力下IHC-AN连接的丢失：噪声性听力损失和听力保持的耳内假体植入，然后测试抗氧化剂(AO)治疗对保护/恢复的有效性，最后确定在抗氧化剂治疗的基础上加用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-检验一种假设，即适度的噪声会导致许多毛细胞的永久性丧失，也会导致许多IHC-AN连接在剩余的IHC上的永久性丧失，并随后导致听神经元(SGN)的丧失。目的2-验证假设(2a)，即有效减少噪声引起的毛细胞丢失的AO治疗在减少IHC-AN连接丢失方面的效果较差，以及(2b)添加特定的抗兴奋毒性治疗将改善IHC-AN连接的保存、SGN和听力的长期存活。目的3-检验假耳植入假体造成的创伤会导致IHC-AN连接丢失的假设，包括毛细胞没有丢失的区域。目的4-验证假说(4a)，即在人工关节置入创伤后加用AO治疗将比IHC-AN连接更有效地保存毛细胞，以及(4b)在AO治疗的基础上加用特异性抗兴奋毒性治疗将改善IHC-AN连接的保存。目的5-验证以下假设：减少IHC-AN连接和SGN的丢失将改善对人工耳蜗刺激的听觉和心理物理反应的空间和时间敏锐度。拟议的研究结果将重新定义和扩大保护听力的治疗目标，不仅适用于治疗两种正在测试的情况，即噪音导致的听力损失和将人工耳蜗植入听力保持不变的耳朵，而且与从耳毒性到前庭疾病等其他内耳疾病的最佳治疗实践高度相关。如果成功，一种新的治疗范例可以直接转化为临床试验，并使全球数百万人受益。 公共卫生相关性：我们建议的研究是为了开发和测试更好的治疗方法，以在两种对耳朵的创伤压力下保护听力，这两种压力是临床上选择的高度相关的：噪声导致的听力损失和听力保持不变的耳朵中的假体植入。

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.