INTERVENTIONS TO PREVENT NOISE INDUCED HEARING LOSS

描述（由申请人提供）：本研究计划的目的是确定氧化应激作为噪声诱导的内耳病理学和听力损失的信号分子的作用，并确定可能减轻噪声诱导的听力损失（NIHL）的新干预措施。以前的工作已经证明了强大的噪声诱导的自由基（活性氧和氮物质，ROS/RNS）的形成和它们在内耳中的分布，在体内，在豚鼠。我们已经显示了用防止自由基形成和抑制自由基或在自由基触发的凋亡途径的其他位点起作用的试剂（例如，阻断凋亡基因）。我们的研究还表明，干预措施，防止自由基形成的Corti器官（而不是侧壁）和衰减NIHL之间的关系。此外，我们已经定义了一种ROS依赖性机制，该机制是长期观察到的噪声诱导的局部血流减少的基础，具有潜在的破坏性后果。这些先前的发现现在导致了一种模型的形成，其中ROS和RNS在内耳中形成，在暴露于高水平的噪声期间和之后，触发导致细胞死亡的多种生化途径，并确定了可以减弱NIHL的干预位点。这一模式构成了当前方案的基础。在本延续项目中，我们将评估药物预防NIHL的疗效在多大程度上依赖于在ROS触发路径沿着不同位点发挥作用的因子的相互作用。我们提出的研究将测试的假设，预防的效果是通过协同作用，跨代理增强。根据最近的研究结果，ROS，特别是RNS的形式后延迟噪声暴露后，表明暴露后治疗可以减弱NIHL，我们将评估RNS和ROS清除剂管理创伤后，以减轻NIHL的疗效。重要的是，我们将评估存活与凋亡诱导途径的强度依赖性程度，以及这如何决定影响噪声后细胞存活的转录因子。我们还将确定血流减少是否会在体内增强NIHL。这些研究将确定新的干预措施和协同作用的网站沿着凋亡途径，以优化预防NIHL。

DESCRIPTION (provided by applicant): The aim of this research program is to define the role of oxidative stress as a signaling molecule for noise induced inner ear pathology and hearing loss and identify new interventions that may attenuate noise induced hearing loss (NIHL). Previous work has demonstrated the robust noise-induced formation of free radicals (both reactive oxygen and nitrogen species, ROS/RNS) and their distribution in the inner ear, in vivo, in the guinea pig. We have shown attenuation of NIHL with agents that prevent formation and scavenge free radicals or function at other sites of free radical-triggered apoptotic pathways (e.g., block apoptotic genes). Our research has also demonstrated a relationship between interventions that prevent free radical formation in the organ of Corti (but not lateral wall) and attenuation of NIHL. In addition we have defined a ROS dependent mechanism that underlies the long observed noise-induced reduction of local blood flow, with potentially damaging consequences. These previous findings now lead to the formulation of a model in which ROS and RNS are formed in the inner ear, during and following exposure to high levels of noise that trigger multiple biochemical pathways leading to cell death, with sites of intervention identified that can attenuate NIHL. This model forms the basis for the current program. In this continuation program we will assess the extent to which drug efficacy in prevention of NIHL is dependent on the interaction of factors that function at varied sites along the ROS-triggered paths. Our proposed studies will test hypotheses that efficacy of prevention is enhanced by synergy across agents. On the basis of most recent findings that ROS and particularly RNS form following a delay after noise exposure, suggesting that post-exposure treatment can attenuate NIHL, we will assess the efficacy of RNS and ROS scavengers administered following trauma to attenuate NIHL. Importantly, we will assess the extent to which survival vs apoptotic induced pathways are intensity dependent, and how this determines the transcription factors that effect cell survival following noise. We will also determine if reduced blood flow potentiates NIHL, in vivo. These studies will define new interventions and synergies at sites along the apoptotic pathway to optimize the prevention of NIHL.