INTERVENTIONS TO PREVENT NOISE INDUCED HEARING LOSS

描述(申请人提供)：本研究计划的目的是明确氧化应激作为噪声诱发内耳病理和听力损失的信号分子的作用，并确定可以减轻噪声诱发听力损失(NIHL)的新干预措施。以前的工作已经证明了噪声诱导的自由基(活性氧和氮物种，ROS/RNS)的形成及其在活体豚鼠内耳中的分布。我们已经展示了用阻止形成和清除自由基的药物或在自由基触发的凋亡途径的其他部位发挥作用的药物(例如，阻断凋亡基因)对NIHL的减弱作用。我们的研究还证明了防止Corti器官(但不是侧壁)自由基形成的干预措施与NIHL减弱之间的关系。此外，我们定义了一种ROS依赖的机制，这种机制是长期观察到的噪音导致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，在该模型中，在暴露于高水平的噪声期间和之后，在内耳形成ROS和RN，这些高水平的噪声触发了导致细胞死亡的多条生化途径，并确定了可以减弱NIHL的干预部位。这一模式构成了当前计划的基础。在这个继续项目中，我们将评估预防NIHL的药物疗效在多大程度上依赖于沿ROS触发路径的不同部位发挥作用的因素的相互作用。我们提议的研究将检验这样的假设，即预防的有效性通过跨药物的协同作用而增强。根据最新的发现，ROS，特别是RNS是在噪声暴露后一段时间后形成的，表明暴露后治疗可以减轻NIHL，我们将评估创伤后使用RNS和ROS清除剂减轻NIHL的效果。重要的是，我们将评估存活和凋亡诱导通路的强度依赖程度，以及这如何决定影响噪音后细胞存活的转录因子。我们还将在体内确定血流减少是否会增强NIHL。这些研究将确定新的干预措施和在细胞凋亡途径上的协同作用，以优化NIHL的预防。

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.