MOLECULAR INTERVENTION PREVENT NOISE INDUCED HEARING LOS

该研究项目的目标是评估氧化应激作为噪声性听力损失（NIHL）因素的作用，NIHL是工业化国家听力损失的主要原因。 噪声引起的内耳代谢活动以及直接的机械性损伤均可导致活性氧（ROS）的产生。 我们提出了一个模型，其中ROS是NIHL的主要致病因素，导致下游级联反应，导致细胞死亡。 该模型提出，噪声诱导ROS的形成，并且ROS及其副产物直接导致内耳组织的病理学，以及间接导致内耳血流减少，从而加剧组织损伤。 该模型还提出了干预措施，可以阻止ROS（抗氧化剂）或其下游级联（神经营养因子，NTF）的形成和直接影响，从而保护内耳免受噪音损伤。 本研究将验证以下假设：1）噪声可诱导ROS和内耳病变，噪声暴露前的抗氧化剂治疗可降低ROS（脂质过氧化）和NAIL（通过豚鼠的电生理学和感觉细胞损伤测量）; 2）耳蜗血流量被异前列腺素（脂质过氧化产物）减少，进一步促进NIHL; 3）NTF将显著降低NIHL，同时最低限度地降低ROS; 3）噪声暴露后处理将提供降低但显著的保护（与预处理相比）。 这些研究旨在确定形成的特定ROS及其形成的时间过程。 它们将使我们能够专门评估抗氧化剂和NTFs减少ROS诱导的细胞破坏的相对有效性。 这些研究将为这种NIHL模型提供关键性测试，并可能导致有效预防NIHL的干预措施。

The goal of this research project is to assess the role of oxidative stress as a factor in noise-induced hearing loss (NIHL), the primary cause of hearing loss in the industrialized world. Noise induced metabolic activity of inner ear as well as direct mechanical trauma may result in the formation of reactive oxygen species (ROS). We propose a model in which ROS represent a major causal factor in NIHL leading to downstream cascades that result in cell death. The model proposes that noise induces the formation of ROS, and that ROS and their byproducts directly cause pathology of the inner ear tissues, as well as indirectly cause a reduction in inner ear blood flow that exacerbates tissue damage. The model also proposes interventions that can block the formation and direct effects of ROS (antioxidants) or their downstream cascades (neurotrophic factors, NTF), and thus may protect the inner ear from noise damage. The studies proposed will test the hypotheses that: 1) noise induces ROS and inner ear pathology, and that antioxidant treatment prior to noise exposure will reduce ROS (lipid peroxidation) and NAIL (measured electrophysiologically and by sensory cell damage in guinea pigs); 2) cochlear blood flow is reduced by isoprostanes, products of lipid peroxidation, further contributing to NIHL; 3) NTF will significantly reduce NIHL while minimally reducing ROS; 3) post noise-exposure treatment will afford reduced, but significant, protection (compared to pretreatment). These studies are geared towards identifying the specific ROS formed and the time course of their formation. They will allow us to specifically assess the relative effectiveness of antioxidants and NTFs to reduce ROS-induced cell destruction. These studies will provide a critical test of this model of NIHL and may lead to interventions that are effective in preventing NIHL.