INTERVENTIONS TO PREVENT NOISE INDUCED HEARING LOSS

描述（由申请人提供）：本研究项目的目的是确定氧化应激作为噪声引起的内耳病理和听力损失的信号分子的作用，并确定可能减轻噪声引起的听力损失（NIHL）的新干预措施。先前的工作已经证明了噪声诱导自由基（活性氧和氮种，ROS/RNS）的形成及其在豚鼠体内内耳中的分布。我们已经证明，使用阻止自由基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位点起作用的药物（例如，阻断凋亡基因）可以减弱NIHL。我们的研究还证明了在Corti器官（但不是侧壁）中阻止自由基形成的干预措施与NIHL的衰减之间的关系。此外，我们还定义了ROS依赖机制，该机制是长期观察到的噪声诱导局部血流量减少的基础，具有潜在的破坏性后果。这些先前的发现现在导致了一个模型的形成，其中ROS和RNS在暴露于高水平噪音期间和之后在内耳形成，高水平噪音触发多种生化途径导致细胞死亡，并确定了可以减轻NIHL的干预位点。这个模型构成了当前程序的基础。在这个后续项目中，我们将评估药物在预防NIHL方面的疗效在多大程度上取决于ros触发路径上不同位点上起作用的因素的相互作用。我们提出的研究将检验假设，即预防效果是通过药物之间的协同作用而增强的。根据最近的研究结果，噪音暴露后延迟形成ROS，特别是RNS，这表明暴露后治疗可以减轻NIHL，我们将评估创伤后给予RNS和ROS清除剂减轻NIHL的效果。重要的是，我们将评估生存与凋亡诱导途径在多大程度上依赖于强度，以及这如何决定影响噪声后细胞存活的转录因子。我们还将确定体内血流量减少是否会增强NIHL。这些研究将确定新的干预措施和协同作用，沿着凋亡途径优化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.